Electrode interface devices for delivery of neuroregenerative therapy

ABSTRACT

Systems, devices and methods are disclosed related to shapeable lead assemblies. Such lead assemblies can be configured to be shaped in a desired manner before and/or during a procedure, such as, for example, after the lead assembly has been at least partially placed within the anatomy of a subject. The shapeable lead assembly can be shaped during a neuroregenerative procedure to contact and/or otherwise interface with a targeted nerve.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part (CIP) of PCT ApplicationPCT/US2020/053630 filed Sep. 30, 2020, which claims priority to U.S.Provisional Application Nos. 62/909,048 filed Oct. 1, 2019 and63/044,208 filed Jun. 25, 2020. This application claims priority to U.S.Provisional Application Nos. 63/044,208 filed Jun. 25, 2020 and63/172,054 filed Apr. 7, 2021. The contents of each of theaforementioned applications are incorporated by reference herein intheir entireties.

FIELD

This application relates generally to devices, systems and methods forlocating and/or treating (e.g., regenerating, facilitating the treatmentof, etc.) injured tissue, and more specifically, to devices, systems andmethods that facilitate the regeneration of injured nerves (e.g.,neuroregeneration) and/or the pain that accompanies nerve injury.

BACKGROUND

Peripheral nerve injuries are severely debilitating, affecting otherwisehealthy patients by limiting their ability to perform activities ofdaily living. Peripheral nerve injuries may result from variousetiologies, from complex trauma to iatrogenic and compressiveneuropathies. However, despite various etiologies the mainstay to repairperipheral nerve damage is surgical repair of transected nerve ends orsurgical release of compressed nerves. Unfortunately, even the bestsurgical procedures usually leave patients with marked deficits. Inaddition, patients often have neuropathic pain associated with a nerveinjury. Pain may be present at the site of injury or radiate along theinjured nerve, or in cases of compression, pain may radiate downstreamfrom the site of injury. Given the disability associated with nerveinjuries, a need clearly exists to improve outcomes.

Currently, clinical treatment of injured peripheral nerves is primarilysurgical, either releasing the source of nerve compression orreattaching the transected nerve directly or with grafting materials.Surgery permits nerve regrowth by re-establishing nerve continuity butfunctional recovery remains inadequate. Generally, nerves regenerateslowly (^(˜)1 mm/day at their fastest) requiring long periods of timebefore reconnecting with denervated target muscle or sensory end-organs.The window of opportunity for nerve regeneration is short with theregenerative capacity of the injured neurons and the regenerativesupport of the distal nerve stump declining with time and distance.These factors together with the misdirection of regenerating nervesaccount for the frequent poor recovery. In addition to poor recovery,patients are often faced with pain resulting from the nerve injury. Thispain may present clinically in the form of allodynia or hyperalgesia.This pain may be transient in nature, resolving when tissue becomesreinnervated or may become chronic if nerve regeneration results in aneuroma formation. Poor regeneration can lead to not only diminishedfunctional motor outcomes, but chronic pain and an increase in residualsensory abnormalities. Enhancing nerve regeneration can result in bettertissue reinnervation which not only improves functional outcomes butreduces the potential for developing chronic or other long-term pain.Chronic or long-term pain can also include pain that persists past anormal healing time (e.g., a normal time vis-à-vis a particular type ofinjury or other source of pain). As used herein, “chronic pain” or“long-term pain” can include, but is not limited to, pain that laststwelve weeks or longer.

SUMMARY

According to some embodiments, an electrical lead assembly configured tobe inserted at least partially within an anatomy of a subject comprisesat least one electrode (e.g., one, two, three, four, more than 4electrodes) configured to be placed adjacent to targeted tissue of thesubject to perform a desired procedure, a first insert located along afirst portion of the lead assembly, wherein the first insert comprisesplastic deformation properties to facilitate a shaping of the leadassembly along the first portion, wherein the first portion isconfigured to substantially maintain a shape following the shaping ofthe lead assembly, wherein the first portion extends to a distal end ofthe lead assembly, and wherein the first portion is configured to beshaped in order to maintain a desired shape and position relative to thetargeted tissue of the subject. The assembly further includes a secondinsert located along a second portion of the lead assembly, wherein arigidity of the second insert is greater than a rigidity of the firstinsert, wherein the second portion extends to a proximal end of the leadassembly, and at least one outer covering configured to extend from theproximal end to the distal end of the lead assembly, wherein the atleast one electrode is located along the first portion of the leadassembly, wherein the proximal end is configured to be inserted into aport of an electrical stimulation device, and wherein the first portionof the lead assembly is configured to be shaped following percutaneousinsertion into the anatomy of the subject by selectively exerting forcesor moment along at least one portion of the first portion.

According to some embodiments, an outer diameter or othercross-sectional dimension of the lead assembly is constant orsubstantially constant along a length of the lead assembly (e.g., withina 5% deviation, except for a possible rounded distal end), the rigidityof the second insert is at least 100 times (e.g., at least 100, 1000,2000, 10000, 15000, 20000, 25000, 30000, etc.) greater than the rigidityof the first insert (e.g., as determined by Young's modules and/orcoefficient of stiffness), and plastic deformation properties of thefirst insert are greater than elastic deformation properties of the atleast one covering.

According to some embodiments, an outer diameter or othercross-sectional dimension of the lead assembly is constant orsubstantially constant along a length of the lead assembly. In someembodiments, a maximum variation in the outer diameter or othercross-sectional dimension is 5% (e.g., 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4to 5%, values between the foregoing values or ranges, etc.) along thelength of the lead assembly.

According to some embodiments, the rigidity of the second insert is atleast 100 times (e.g., at least 100, 1000, 2000, 10000, 15000, 20000,25000, 30000, etc.) greater than the rigidity of the first insert.

According to some embodiments, the proximal end comprises at least oneelectrical contact that extends to an exterior of the lead assembly,wherein the at least one electrical contact is electrically coupled tothe at least one electrode along the first portion of the lead assembly.In some embodiments, the proximal end is configured to be inserted(e.g., directly inserted) into a port of an electrical stimulationdevice without the need for an additional connector or component.

According to some embodiments, plastic deformation properties of thefirst insert are greater than elastic deformation properties of the atleast one covering. In some embodiments, the first insert extends to ornear a distal end of the second insert. In some embodiments, the firstinsert does not extend to or near a distal end of the second insert.

According to some embodiments, the at least one electrode comprises aproximal electrode and a distal electrode, wherein the proximal anddistal electrodes are located along the first portion of the leadassembly (e.g., located along a distal one-half, one-third orone-quarter of the lead assembly).

According to some embodiments, the at least one outer covering comprisesa single member that extends from the proximal end to the distal end ofthe lead assembly. In some embodiments, the at least one outer coveringcomprises at least two separate members that form a substantiallyseamless surface along an exterior of the lead assembly. In someembodiments, the at least one outer covering along the proximal end ofthe lead assembly comprises a color that is different than a distalportion of the at least one outer covering.

According to some embodiments, the first portion of the lead assembly isconfigured to be shaped using forceps.

According to some embodiments, a distal aspect or portion of the outercovering comprises a lower durometer or hardness than a proximal aspectof the outer covering. In some embodiments, a Shore D durometer of thedistal aspect of the outer covering is between 20D and 50D, wherein aShore D durometer of proximal aspect of the outer covering is between50D and 80D, and wherein a thickness of the outer covering is between100 and 400 μm.

According to some embodiments, the first insert comprises an annealedmetal or alloy. In some embodiments, the first insert is electricallycoupled to a wire. In some embodiments, the second insert is physicallycoupled to an insulative material. In some embodiments, the secondinsert comprises a non-annealed metal. In some embodiments, the secondinsert provides a backbone for a connector set. In one embodiment, theconnector set is operatively coupled to a stimulator.

According to some embodiments, a diameter or other cross-sectionaldimension of the insert is 100% to 500% of the thickness of the outercovering. In some embodiments, the outer diameter through the length ofthe electrical lead assembly is uniform to facilitate removal of shaftsor tools.

According to some embodiments, a Shore D durometer of the outer coveringis between 20D and 80D, a thickness of the outer covering is between 100and 400 μm, the first insert comprises an annealed metal or alloy, and adiameter or other cross-sectional dimension of the insert is 100% to500% of the thickness of the outer covering. In some embodiments, theannealed metal or alloy comprises copper.

According to some embodiments, a diameter or other cross-sectionaldimension of the insert is 100% to 500% of the thickness of the outercovering.

According to some embodiments, the outer covering comprises a uniform orcontinuous (e.g., or substantially uniform or continuous) thicknessthrough a length of the electrical lead assembly.

According to some embodiments, a distal aspect of the outer coveringcomprises a lower durometer or hardness than a proximal aspect of theouter covering. In some embodiments, a Shore D durometer of the distalaspect of the outer covering is between 20D and 50D. In someembodiments, a Shore D durometer of proximal aspect of the outercovering is between 50D and 80D. In some embodiments, a Shore Ddurometer of the outer covering is between 20D and 80D. In someembodiments, a thickness of the outer covering is between 100 and 400μm.

According to some embodiments, the first insert comprises an annealedmetal or alloy. In some embodiments, the annealed meal or alloycomprises copper. In some embodiments, a diameter or othercross-sectional dimension of the insert is 100% to 500% of a thicknessof the outer covering.

According to some embodiments, the lead assembly is configured to atleast partially surround a targeted nerve or nerve bundle. In someembodiments, the lead assembly is configured to be used during aneuroregenerative procedure. In some embodiments, the lead assembly isconfigured to be used during a pain management procedure. In someembodiments, the lead assembly is configured to be used during a both aneuroregenerative procedure and a pain management procedure.

According to some embodiments, an electrical lead assembly configured tobe inserted at least partially within an anatomy of a subject includesat least one electrode, an insert (e.g., a distal insert) located alonga distal portion of the lead assembly, wherein the insert comprisesplastic deformation properties to facilitate a shaping of the leadassembly along the distal portion, wherein the distal portion isconfigured to substantially maintain a shape following the shaping ofthe lead assembly, wherein the distal portion extends to a distal end ofthe lead assembly, and at least one outer covering configured to extendfrom a proximal end to the distal end of the lead assembly, whereinplastic deformation properties of the insert are greater than elasticdeformation properties of the at least one covering, wherein the atleast one electrode is located along the distal portion of the leadassembly, wherein the distal portion of the lead assembly is configuredto be shaped following percutaneous insertion into the anatomy of thesubject by selectively exerting forces or moment along at least oneportion of the first portion, and wherein an outer diameter or othercross-sectional dimension of the lead assembly is constant orsubstantially constant along a length of the lead assembly.

According to some embodiments, a maximum variation in the outer diameteror other cross-sectional dimension is 5% along the length of the leadassembly.

According to some embodiments, the proximal end of the lead assemblycomprises a proximal insert, the proximal insert being more rigid thanthe insert (e.g., distal insert). In some embodiments, the rigidity ofthe proximal insert is at least 100 times greater than the rigidity ofthe insert. In some embodiments, the proximal end is configured to beinserted into a port of an electrical stimulation device. In someembodiments, the proximal end is configured to be inserted into a portof an electrical stimulation device without the need for an additionalconnector or component.

According to some embodiments, the at least one electrode comprises aproximal electrode and a distal electrode, wherein the proximal anddistal electrodes are located along a distal one-third of the leadassembly.

According to some embodiments, the at least one outer covering comprisesa single member that extends from the proximal end to the distal end ofthe lead assembly. In some embodiments, the at least one outer coveringcomprises at least two separate members that form a substantiallyseamless surface along an exterior of the lead assembly.

According to some embodiments, a method of managing pain related to aperipheral nerve injury of a subject comprises delivering stimulationenergy of a first frequency to the target nerve via at least oneelectrode assembly during a regenerative phase, wherein delivering saidstimulation energy creates a neuroregenerative effect to the targetnerve resulting in enhanced tissue reinnervation, wherein the enhancedtissue reinnervation is configured to result in a reduced potential fordeveloping long-term pain, and delivering stimulation energy of a secondfrequency for a predetermined period via the at least one electrodeassembly during at least one neuropathic pain management phase, whereindelivering stimulation energy during the at least one neuropathic painmanagement phase alleviates neuropathic pain of the subject caused bythe peripheral nerve injury.

According to some embodiments, the method additionally comprisingaccessing a target nerve using a para-incisional approach, wherein thetarget nerve is a peripheral nerve that has sustained injury, whereinthe frequency of the neuropathic pain management phase is greater thanthe frequency of the neuroregenerative phase.

According to some embodiments, the method further comprises accessing atarget nerve using a para-incisional approach, wherein the target nerveis a peripheral nerve that has sustained injury.

According to some embodiments, the frequency of the neuropathic painmanagement phase is greater than the frequency of the neuroregenerativephase. In some embodiments, pain management therapy comprisesstimulation in the 50 to 200 Hz range (e.g., 50-60, 50-55, 55-60, 52-58Hz, values between the foregoing ranges, etc.). In some embodiments, thefrequency of the neuropathic pain management phase is 20 KHz to 500 KHz.In some embodiments, the frequency of the neuropathic pain managementphase is 1 KHz to 10 KHz.

According to some embodiments, accessing the target nerve is performedpercutaneously.

According to some embodiments, delivering stimulation energy during theregenerative phase is sufficient to elicit a response. In someembodiments, the response relates to an action potential or an evokedresponse in the subject. In some arrangements, the elicited responseduring the regenerative phase is configured to, at least in part,confirm validation of therapeutic efficacy of neuroregenerative therapyin the subject.

According to some embodiments, delivering stimulation energy during theneuropathic pain management phase is sufficient to elicit a response. Insome arrangements, the response relates to an action potential or anevoked response in the subject. In some embodiments, the elicitedresponse during the neuropathic pain management phase is configured to,at least in part, confirm relief from neuropathic pain in the subject.

According to some embodiments, a system comprises one or more componentsconfigured to deliver stimulation energy of the first frequency and thesecond frequency to accomplish any one of the methods described above.

According to some embodiments, the systems and methods disclosed hereinare configured to provide a targeted approach to both treating injuredtissue and reducing neuropathic pain with electrical stimulation byenhancing tissue reinnervation.

In some embodiments, the systems described herein may deliver one ormore bouts of neuroregenerative therapy and separate pain managementtherapy. In other arrangements, multiple bouts of neuroregenerativetherapy may be delivered that lead to enhanced tissue reinnervation. Insuch embodiments, a diminished potential for developing chronic pain orother long-term pain can result for a patient or other subject whileapplying pain management waveforms may reduce short-term acute pain.

According to some embodiments, a system (and corresponding method)configured to deliver targeted electrical stimulation therapy to injurednerves is amenable to fit the needs of different injuries and clinicalworkflows, including different anatomical areas, injured nerves, nervediameters, and types of nerve injury. The system can advantageouslyprovide users with the ability to seamlessly interchange nerveinterfaces to connect with and deliver neuroregenerative therapy (e.g.,for neuroregeneration). The embodiments disclosed herein provideflexibility to users to apply neuroregenerative therapy prior tosurgery, at the time of surgery, post-surgery, or a combination thereof,as desired or required.

According to some embodiments, additionally, the systems and methodsallow for confirmation that the stimulating electrodes are functioningcorrectly by providing a means to verify the integrity of the electrodeand/or system either through a physical self-verification or automaticverification steps. This becomes advantageous in situations where motornerves are transected and no physical response (e.g., no musclecontraction) is present or in situations where a pure sensory nerve istransected and there are no physical responses to begin with. This sameverification method allows for safe and continuous delivery ofneuroregenerative therapy by monitoring current flow through theelectrodes.

According to some embodiments, the systems and methods disclosed hereinfurther allow users to perform nerve location tasks using the same ordifferent nerve interfaces prior to commencing neuroregenerativetherapy. The system is also configured to incorporate a single buttonthat controls stimulus parameters, system modes, and therapy timeproviding an easy to use interface for a clinician minimizing trainingand complexity.

According to some embodiments, a method of stimulating a target nerve ofa subject comprises, during a first phase, delivering stimulation energyof a first frequency via at least one electrode assembly, and, during asecond phase, delivering to the subject stimulation energy of a secondfrequency for a predetermined period via the at least one electrodeassembly, wherein delivering stimulation energy to the subject duringthe second phase creates a regenerative effect (e.g., neuroregenerativeeffect) to the target nerve, and wherein delivering stimulation energyduring the first phase is configured to confirm at least one validationcondition. In some embodiments, the second frequency is greater than thefirst frequency.

According to some embodiments, a method of stimulating a target nerve ofa subject comprises, during a first phase, delivering stimulation energyof a first frequency via at least one electrode assembly, and, during asecond phase, delivering to the subject stimulation energy of a secondfrequency for a predetermined period via the at least one electrodeassembly, wherein delivering stimulation energy to the subject duringthe second phase creates a neuroregenerative effect to the target nerve,and wherein the second frequency is greater than the first frequency.

According to some embodiments, the at least one validation condition isthat the at least one electrode assembly is working. In someembodiments, delivering stimulation energy during the first phase isconfigured to activate an indicator that the at least one electrodeassembly is working. In some embodiments, the indicator comprises avisual indicator (e.g., a LED or other light source). In otherarrangements, the indicator comprises a non-visual indicator (e.g., anaudible indicator, a haptic feedback indicator, etc.).

According to some embodiments, the at least one validation condition isthat the at least one electrode is contacting the target nerve. In someembodiments, delivering stimulation energy during the first phase isconfigured to facilitate locating the target nerve. In some embodiments,delivering stimulation energy at a first frequency during the firstphase creates a visible and/or verbal (e.g., oral) response from thesubject. In several embodiments, the visible response comprises atwitch, reflex, muscle response or other involuntary bodily movement.

According to some embodiments, the predetermined period is at least 10minutes. In some embodiments, the predetermined period is at least 20minutes or 30 minutes. In some arrangements, the predetermined period is10 minutes to 60 minutes.

According to some embodiments, the first frequency is 1 Hz to 40 Hz. Insome embodiments, the first frequency is lower than 40 Hz. In someembodiments, the second frequency is 1 Hz to 100 Hz. In someembodiments, the first frequency is 1 Hz to 10 Hz, and wherein thesecond frequency is 10 Hz to 100 Hz.

According to some embodiments, the method further comprises positioningthe at least one electrode assembly adjacent the target nerve of thesubject.

The method additionally includes at least partially securing the atleast one electrode assembly to the target nerve of the subject. In someembodiments, at least partially securing the at least one electrodeassembly to the target nerve comprises using at least one of a suture, abarb, a tissue anchor, a flap and another type of mechanical connector.In one embodiment, at least partially securing the at least oneelectrode assembly to the target nerve comprises using an adhesive.

According to some embodiments, positioning the at least one electrodeassembly adjacent the target nerve comprises not fastening the at leastone electrode assembly to the subject. In some embodiments, whereinpositioning the at least one electrode assembly adjacent the targetnerve comprises aligning the at least one electrode assembly adjacent ornear the target nerve (e.g., with or without the aid of an insertiontool).

According to some embodiments, wherein delivering stimulation energy tothe subject during the first phase comprises delivering the stimulationenergy in a repetitive burst sequence. In some embodiments, whereinrepetitive burst sequence comprises at least two pulses. In someembodiments, wherein repetitive burst sequence comprises at least threepulses.

According to some embodiments, wherein the at least one electrode isincluded as part of a bipolar electrode assembly. In some embodiments,wherein positioning the at least one electrode assembly at or adjacentthe target nerve comprises advancing the at least one electrode assemblyand a lead secured to the at least one electrode through a cannula,sheath or other device with an internal opening. In some embodiments, inintraoperative settings, the at least one electrode assembly comprises acuff electrode.

According to some embodiments, a device for stimulating a target nerveof a subject comprises at least one electrode assembly, and a leadphysically coupled to the at least one electrode assembly, wherein,during a first phase, the at least one electrode is configured todeliver stimulation energy of a first frequency via at least oneelectrode assembly, wherein, during a second phase, the at least oneelectrode is configured to deliver to the subject stimulation energy ofa second frequency for a predetermined period via the at least oneelectrode assembly, wherein delivery of stimulation energy to thesubject during the second phase creates a neuroregenerative effect tothe target nerve, and wherein delivery of stimulation energy to thesubject during the first phase is configured to confirm at least onevalidation condition.

According to some embodiments, the at least one validation condition isthat the at least one electrode assembly is working. In someembodiments, the device further comprises an indicator, whereindelivering stimulation energy during the first phase is configured toactivate the indicator, the indicator being configured to provideconfirmation that the at least one electrode assembly is working. Insome embodiments, the indicator comprises a visual indicator (e.g., aLED or other light source). In some embodiments, the indicator comprisesa non-visual indicator (e.g., an audible indicator, a haptic feedbackindicator, etc.).

According to some embodiments, the at least one validation condition isthat the at least one electrode is contacting the target nerve. In someembodiments, the delivery of stimulation energy during the first phaseis configured to facilitate locating the target nerve. In someembodiments, the delivery of stimulation energy at a first frequencyduring the first phase creates a visible and/or verbal (e.g., oral)response from the subject. In some embodiments, the visible responsecomprises a twitch, reflex, muscle response or other involuntary bodilymovement.

According to some embodiments, the first frequency is 1 Hz to 40 Hz. Insome embodiments, the first frequency is lower than 40 Hz. In someembodiments, the second frequency is 1 Hz to 100 Hz. In someembodiments, the first frequency is 1 Hz to 10 Hz, and wherein thesecond frequency is 10 Hz to 100 Hz.

According to some embodiments, the delivery of stimulation energy to thesubject during the first phase comprises delivering the stimulationenergy in a repetitive burst sequence. In some embodiments, therepetitive burst sequence comprises at least two pulses. In someembodiments, the repetitive burst sequence comprises at least threepulses. In some embodiments, the least one electrode assembly comprisesa cuff electrode.

According to some embodiments, a method of stimulating a target nerve ofa subject comprises identifying the target nerve, positioning at leastone electrode assembly relative to the subject to selectively stimulatethe target nerve, and delivering therapeutic stimulation energy to thesubject via the at least one electrode assembly for a predetermined timeperiod to create a neuroregenerative effect to the target nerve, whereinthe predetermined time period is at least 10 minutes (e.g., 10 minutes,10-30 minutes, 10-60 minutes, etc.), and wherein the at least oneelectrode assembly comprises a first electrode positioned immediatelyadjacent the target nerve and a second electrode, the second electrodebeing positioned physically apart from the first electrode.

According to some embodiments, the second electrode comprises a patchelectrode positioned on a skin surface of the subject. In oneembodiment, the first and second electrodes are included as part of abipolar electrode assembly. In some embodiments, identifying the targetnerve comprises soliciting a response from the subject via delivery of avalidation stimulus to the subject. In some embodiments, the validationstimulus comprises a frequency that is lower than a frequency of thetherapeutic stimulation energy. In some embodiments, the validationstimulus comprises a repetitive burst sequence with at least two pulses.In some embodiments, the repetitive burst sequence comprises at leastthree pulses.

According to some embodiments, a method of stimulating a target nerve ofa subject comprises identifying the target nerve, positioning at leastone electrode assembly adjacent to the target nerve, prior topositioning the at least one electrode assembly adjacent to the targetnerve, validating that the at least one electrode is electricallyactivated when subjected to a validation stimulus, wherein thevalidation stimulus originates from a validation stimulus source, anddelivering therapeutic stimulus to the subject via the at least oneelectrode assembly for a predetermined time period to create aneuroregenerative effect to the target nerve, wherein the therapeuticstimulus originates from a therapeutic stimulus source, wherein thepredetermined time period is at least 10 minutes.

According to some embodiments, the validation stimulus source is thesame as the therapeutic stimulus source, such that the validationstimulus source and the therapeutic stimulus source comprise a singlestimulus course. In some embodiments, the single stimulus sourcecomprises a handheld device. In some embodiments, the validationstimulus source is different from the therapeutic stimulus source. Insome embodiments, the validation stimulus comprises lower frequency thanthe therapeutic stimulus. In some embodiments, the validation stimuluscomprises a repetitive burst sequence with at least two pulses. In someembodiments, the repetitive burst sequence comprises at least threepulses (e.g., 3, 4, 5 pulses, more than 5 pulses, etc.).

According to some embodiments, the present application discloses anelectrical stimulation system comprising one or more electrodes that maybe used for intra-operative or peri-operative nerve stimulation. In someembodiments, the system comprises a relatively small size, suitable tofit into the palm of an end-user. In some embodiments, one or more ofthe configurations disclosed herein provide the ability to interface thesystem with different electrodes. In some embodiments, the system isdesigned to be single use and disposable providing end-users, such assurgeons or other practitioners, the ability to use the systemintraoperatively (e.g., provided the system is sterilized and packagedin appropriate packaging material).

In some embodiments, the various systems, devices and methods disclosedherein provide a practitioner with a way of locating a damaged nerve andtreating it with electrical stimulation. The embodiments can be usedintra-operatively or peri-operatively.

In some embodiments, the system can be used in peri-operative settings.The housing of the system can include controls (e.g., one or more setsof controls) to change the stimulus amplitude and/or other settings.

In some embodiments, the system comprises one or more controls to start,stop, pause, restart and/or otherwise alter the delivery of energy toheal injured tissue. In some embodiments, the system additionallycomprises circuitry to enable power to the system and thus providestimulation only when the appropriate interface has been connected.Visual indicators may be included on the housing or the connectedinterface. These indicators may provide end-users with signals relayinginformation regarding the status of the system, the active interfaceuse, the mode it is operating in, the stimulus settings, and/or the timeremaining on the delivery of the treatment. The indicators may comprisemultiple light emitting diodes, graphical displays, or similar emissiveelements. The housing also may contain an element used to secure thesystem to a surgical drape or other structure. This element may be butis not limited to an adhesive, strap, hook, or clip.

Additional aspects of the system include the ability to provide eithermonopolar or bipolar stimulation. In the case of intraoperative use,where the exposed injured tissue is preferably a nerve, the system maybe deployed using a bipolar or monopolar electrode apparatus tointerface with the injured nerve. The described electrode apparatus mayallow the user to interface any diameter nerve by wrapping the electrodecarrier body around the nerve and securing the wrapped portion in placeusing tabs. Lateral deflection of the tabs releases the wrapped nerveallowing easy removal of the electrode. One aspect of the electrodeapparatus is that it is molded in a flat or open configuration allowingthe electrode to spring back to this configuration when wrapped around anerve. Molded tabs on the electrode allow the head portion of theelectrode to be secured underneath them preventing the electrode tospring back to its flat configuration and maintaining a wrap around theinterfaced nerve to deliver the appropriate stimulation treatment.

In some embodiments, for peri-operative use, an electrode is placedeither during a surgical procedure or peri-operatively using apercutaneous method. In some embodiments, a monopolar electrode can beused where the electrode interface may not be in contact with the nervedirectly. In such arrangements, the system can connect or otherwisecouple to a return electrode (e.g., which can include a patch typeelectrode placed on the skin and connected to the system directly).

According to some embodiments, additional aspects of the system includea stimulation signal (e.g., that may comprise either constant voltage orconstant current pulses). In some embodiments, a constant current pulseis used. In some embodiments, constant current stimulation amplitudesrange from 0 to 20 milliamperes (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6,6-7, 7-8, 8-9, 9-10, 10-15, 15-20 milliamperes, values within theforegoing ranges, etc.).

According to some embodiments, for safe stimulation over a period atime, biphasic pulse outputs are used. This can help ensure that no netcharge is being delivered at the electrode interface. In someembodiments, charge balancing is accomplished using a passive element(e.g., such as a capacitor coupled to the output of the stimulator). Insome embodiments, active methods sample the output offset of thestimulator in a feedback loop and/or correct this either by generatingadditional pulses of the correct polarity or injecting a reverse offsetto ensure that the net charge is zero. Other methods not specificallydescribed herein may also be employed.

According to some embodiments, additional aspects of the system includea test mode (e.g., to allow the user to first deliver low-frequencystimulation (e.g., from 0.1 to 10 Hz) that permits the end-user tovisualize if the injured tissue responds to stimulation). In someembodiments, the various configurations enable the user to adjust thestimulus output to a desired level and initiate the therapeutic deliveryof electrical stimulation. Additional parameters can be adjusted.

According to some embodiments, additional aspects of the system includea modification of the first phase of stimulation and housing toaccommodate a bipolar probe electrode to serve as a nerve locator. Insome embodiments, the test mode can be modified to deliver electricalstimulation pulses sufficient to elicit a strong muscle contractileresponse following probe connection with a peripheral nerve. In severalarrangements, the test mode provides stimulation doublet pulses (e.g.,doublets) used to exploit the muscle catch-like property wheresuccessive stimuli lead to fused contractions. In certain embodiments,doublets allow for a greater muscle excursion and can be helpful innerve location.

According to some embodiments, a method for treating injured tissue(e.g., nerve) comprises first interfacing tissue with an electrodesuitable to the use-case (e.g., intra or peri-operative, otherprocedure, etc.). The method can also comprise securing or otherwisecoupling an electrode to the system. In some embodiments, the system isthen enabled to provide test stimulation to verify the responsiveness ofthe tissue to electrical stimulation. In some embodiments, the system isconfigured to permit the user to modify one or more operationalparameters (e.g., amplitude). The method further includes the userinitiating neuroregenerative therapy to treat the injured tissue (e.g.,targeted nerve).

According to some embodiments, the methods disclosed herein areconfigured to provide a targeted approach to treating injured tissuewith electrical stimulation. In some embodiments, unlike otherstimulation systems, the systems, devices and methods disclosed hereincan be configured to enable users to choose whether to apply the systemintraoperatively using a pre-determined suitable electrode interface orperi-operatively using a suitable electrode interface. In someembodiments, the length of a surgical procedure will determine how thedevice is applied.

According to some embodiments, a method of placing an electrical leadassembly at least partially within an anatomy of a subject comprisespercutaneously inserting the electrical lead assembly within the anatomyof the subject, the lead assembly comprising at least one electrodeconfigured to contact targeted tissue of the subject to perform adesired procedure, wherein the electrical lead assembly furthercomprises an insert and outer covering, wherein the insert compriseselastic deformation properties to facilitate shaping or re-shaping ofthe electrical lead assembly, and wherein the outer covering compriseselastic deformation properties to permit the outer covering to undergo atemporary change in shape once a force is exerted on the electrical leadassembly. The method further comprises shaping the electrical leadassembly after percutaneous insertion into the anatomy of the subject byselectively exerting forces or moment along at least one portion of theelectrical lead assembly, wherein the elastic deformation properties ofthe outer covering are not greater than (e.g., are equal to or lessthan) the plastic deformation properties of the insert, and whereinshaping the electrical lead assembly can place the at least oneelectrode of the electrical lead assembly along the targeted tissue.

According to some embodiments, the desired procedure comprises aneuroregenerative procedure and/or pain management procedure. In someembodiments, the targeted tissue comprises nerve tissue.

According to some embodiments, an electrical lead assembly configured tobe inserted at least partially within an anatomy of a subject comprisesat least one electrode configured to contact targeted tissue of thesubject to perform a desired procedure, an insert, wherein the insertcomprises elastic deformation properties to facilitate shaping orre-shaping of the electrical lead assembly, and an outer covering,wherein the outer covering comprises elastic deformation properties topermit the outer covering to undergo a temporary change in shape once aforce is exerted on the electrical lead assembly, wherein the electricallead assembly is configured to be shaped following percutaneousinsertion into the anatomy of the subject by selectively exerting forcesor moment along at least one portion of the electrical lead assembly.

According to some embodiments, a shapeable lead assembly is configuredto be shaped in a desired manner before and/or during a procedure, suchas, for example, after the lead assembly has been at least partiallyplaced within the anatomy of a subject. The shapeable lead assembly canbe shaped during a neuroregenerative procedure to contact and/orotherwise interface with a targeted nerve.

According to some embodiments, a shapeable lead assembly includes aninsert or other member and an outer jacket or other outer covering. Theinsert can be configured to facilitate shaping or re-shaping of theassembly and can include plastic deformation properties (e.g., theinsert can be configured for distortion that occurs when a material issubjected to certain forces and/or stresses that exceed its yieldstrength and cause it to elongate, bend, twist and/or the like. Such adistortion can be temporary, such that the insert or other member canmaintain its shape when no external forces are exerted on it (e.g., asit sits on a table or other surface, until a user exerts another bendingor other re-shaping force or moment, etc.). The outer jacket or otherouter covering of the lead assembly can include elastic deformationproperties (e.g., is configured to undergo a temporary change in shapeonce a force is exerted on the lead assembly, and thus the outer jacketor covering). Such members with elastic deformation properties areconfigured to reassume their original shape or orientation (e.g., are atleast partially self-reversing) once the force or moment is removed orreduced.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects and advantages of the presentapplication are described with reference to drawings of certainembodiments, which are intended to illustrate, but not to limit, theconcepts disclosed herein. The attached drawings are provided for thepurpose of illustrating concepts of at least some of the embodimentsdisclosed herein and may not be to scale.

FIG. 1 illustrates a schematic of various configurations of the systemaccording to one embodiment;

FIG. 2A illustrates a top view of a hand-held nerve locator according toone embodiment;

FIG. 2B illustrates a top view of a hand-held nerve locator according toone embodiment incorporating lateral grooves to facilitate holding usingone hand;

FIG. 2C illustrates a side view of a hand-held nerve locator accordingto one embodiment incorporating a vertical groove to facilitate rotationand access to controls using one hand;

FIG. 2D illustrates a rear view of the hand-held nerve locator accordingto one embodiment showing access to the nerve port;

FIG. 3 illustrates an oblique view of a modified touchproof jackaccording to one embodiment used to provide a contact for jack detectioncircuitry;

FIG. 4 illustrates a schematic of jack detection circuitry according toone embodiment configured to detect medical touchproof connections;

FIG. 5 illustrates a schematic view of the main microcontroller andsub-systems that interact with the microcontroller to create the systemaccording to one embodiment;

FIG. 6A illustrates a graph depicting doublet stimulus pulses at anarbitrary amplitude according to one embodiment;

FIG. 6B illustrates a graph depicting bi-phasic doublet stimulus pulsesat an arbitrary amplitude according to one embodiment;

FIG. 6C illustrates a graph depicting using a single charge balancingpulse following a doublet stimulus pulse at an arbitrary amplitudeaccording to one embodiment;

FIG. 6D illustrates a graph depicting exponentially rising chargebalancing pulses following each pulse in a doublet pulse train at anarbitrary amplitude according to one embodiment;

FIG. 7A illustrates a perspective view of an embodiment of the apparatuswhere the electrode configuration is monopolar with a single electrodepad being present in the thickest portion of the carrier according toone embodiment;

FIG. 7B illustrates a cross-sectional view of the carrier showing theattachment of the single electrode pad to a lead wire with the lead wirebeing externalized from the carrier at the tail portion according to oneembodiment;

FIG. 8A illustrates a perspective view of the apparatus with lead cableexiting the carrier along the longitudinal axis from the tail end of thecarrier according to one embodiment;

FIG. 8B illustrates a perspective view of the locking mechanism beingengaged with the carrier being wrapped around a tubular structureaccording to one embodiment;

FIG. 8C illustrates a perspective view of the apparatus with lead cableexiting the carrier perpendicular to the longitudinal axis according toone embodiment;

FIG. 9A illustrates a rear view of the apparatus showing a singlethrough-hole starting at the tail portion of the apparatus and used toplace an electrode according to one embodiment;

FIG. 9B illustrates a perspective view of the apparatus shown in FIG. 3Aand highlights the exit portion of the through-hole;

FIG. 10A illustrates a perspective view of one embodiment of theapparatus where the electrode configuration is bipolar with twoelectrode pads according to one embodiment;

FIG. 10B illustrates a perspective view of one embodiment of theapparatus where the electrode configuration is tripolar with threeelectrode pads according to one embodiment;

FIG. 11A illustrates a perspective view of one embodiment of theapparatus where the electrode configuration is bipolar with twoelectrode pads that are made from metallic foil and oriented in alongitudinal direction along the grooved portion of the carrieraccording to one embodiment;

FIG. 11B illustrates a perspective view of one embodiment of theapparatus where the electrode configuration is tripolar with threeelectrode pads that are made from metallic foil and oriented in alongitudinal direction along the grooved portion of the carrieraccording to one embodiment;

FIG. 11C illustrates a closer perspective view of one embodiment of theapparatus where the electrode configuration is bipolar with twoelectrode pads that are made from metallic foil and oriented in alongitudinal direction along the grooved portion of the carrieraccording to one embodiment;

FIG. 12 illustrates a perspective view of an embodiment where thelocking mechanism is a circular strap according to one embodiment;

FIG. 13 illustrates a perspective view of an embodiment where thelocking mechanism is a set of paired apertures arranged longitudinallyalong the carrier and one pair of protrusions or buttons that engagewith the apertures according to one embodiment;

FIG. 14 illustrates a perspective view of an embodiment where anadhesive patch containing a visual indicator is coupled to the proximalend of the lead wire of the electrode apparatus according to oneembodiment;

FIG. 15A illustrates a perspective view of an embodiment where anadhesive patch is coupled to a monopolar needle electrode with the patchserving as a return according to one embodiment;

FIG. 15B illustrates a top view of the circuitry layer of the adhesivepatch stimulator according to one embodiment;

FIG. 15C illustrates an exploded view of the assembly of the adhesivepatch stimulation system incorporating a conductive rubber skininterface, a circuitry layer and a elastomeric protective layeraccording to one embodiment;

FIG. 16A illustrates a perspective view of an embodiment of theapparatus showing the carrier coupled to a polymer background materialused for isolating a tissue of interest from surrounding tissueaccording to one embodiment;

FIG. 16B illustrates a perspective view of an embodiment of theapparatus showing the carrier coupled to a polymer background materialused for isolating a tissue of interest from surrounding tissue with atransected nerve situated on the background material according to oneembodiment;

FIG. 16C illustrates a perspective view of an embodiment of theapparatus showing the carrier being folded to wrap the nerve while stillpartially coupled to a polymer background material used for isolating atissue of interest from surrounding tissue with a transected nervesituated on the background material according to one embodiment;

FIG. 17A illustrates one embodiment of an electrical lead;

FIG. 17B illustrates one embodiment of an electrical lead;

FIG. 17C illustrates one embodiment of an electrical lead;

FIG. 17D illustrates one embodiment of an electrical lead;

FIG. 18A illustrates one embodiment of an electrical lead coupled to acap element;

FIG. 18B illustrates one embodiment of a cap element comprisingelectrical circuitry;

FIG. 18C illustrates one embodiment of an assembly configured to besecured to a cap element;

FIG. 18D illustrates the assembly of FIG. 18C secured to the cap elementof FIG. 18B;

FIG. 18E illustrates one embodiment of an electrical lead comprising acap element;

FIG. 19 illustrates one embodiment of an adhesive patch that includes anexposed conductive contact;

FIG. 20A illustrates one embodiment of a verification assembly thatincludes a conductive element;

FIG. 20B illustrates one embodiment of a cuff electrode apparatus thatis interfaced with the verification bar;

FIG. 20C illustrates one embodiment of a cuff electrode apparatus thatis interfaced with the verification bar;

FIG. 20D illustrates one embodiment of a cuff electrode apparatus thatis interfaced with the verification bar;

FIGS. 21A and 21B illustrate one embodiment of an electrode comprisingof a percutaneous lead coupled to a housing including a stimulationsource;

FIG. 21C illustrates one embodiment of an electrode comprising of apercutaneous lead coupled to a housing including a stimulation source;

FIGS. 22 and 23 include flow diagrams illustrating two differentembodiments of methods for using the systems and devices disclosedherein;

FIG. 24 is a flow diagram illustrating the process of locating andtreating an injured nerve in an intraoperative setting using thedescribed system according to one embodiment;

FIG. 25 is a flow diagram illustrating the process of locating andtreating an injured nerve in an intraoperative setting using the systemsand devices disclosed herein according to another embodiment;

FIG. 26 is a flow diagram illustrating the process of locating andtreating an injured nerve using the systems and devices disclosed hereinaccording to another embodiment;

FIGS. 27A to 27E illustrates one embodiment of a procedural diagramdepicting a process of inserting an electrode percutaneously using aninsertion tool and connection a stimulator to deliver neuroregenerativetherapy;

FIGS. 28A to 28D illustrate embodiments of placing an electrodepercutaneously in different anatomical locations to deliverneuroregenerative therapy;

FIGS. 29A to 29D illustrate embodiments of stimulating and measuring oneor more biological signals using a percutaneously-placed electrode leadconnected to a surface patch with integrated electronics; and

FIG. 29E illustrates one embodiment of stimulating using apercutaneously-placed electrode lead and measuring a biological signalusing a cuff electrode around a nerve with both connected to a surfacepatch with integrated electronics;

FIG. 30 illustrates a schematic view of how a multi-channel electrodemay be interfaced with the system according to one embodiment;

FIG. 31 schematically illustrates a flowchart of a procedure, protocolor method for delivering neuroregenerative and pain management therapyto a subject according to one embodiment;

FIG. 32 schematically illustrates a flowchart of a procedure, protocolor method for delivering neuroregenerative and pain management therapyto a subject according to one embodiment;

FIG. 33 schematically illustrates a flowchart of a procedure, protocolor method for delivering neuroregenerative and pain management therapyto a subject according to one embodiment;

FIG. 34 schematically illustrates a flowchart of a procedure, protocolor method for delivering neuroregenerative and pain management therapyto a subject according to one embodiment;

FIG. 35 illustrates one embodiment of a pain reducing waveform appliedby a stimulation system;

FIG. 36 illustrates one embodiment of a system configured to provideboth neuroregenerative therapy and pain management therapy to a subject;

FIG. 37A illustrates a perspective view of an electrode lead beingshaped by hand within a surgical field according to one embodiment;

FIG. 37B illustrates a perspective view of an electrode lead beingshaped using forceps within a surgical field according to oneembodiment;

FIG. 38A illustrates a perspective view of an electrode lead that hasbeen shaped with the shape deviating from the general longitudinal axisof the lead body according to one embodiment;

FIG. 38B illustrates a perspective view of an electrode lead that hasbeen shaped to generally surround or wrap around a nerve structureaccording to one embodiment;

FIG. 38C illustrates a perspective view of an electrode lead that hasbeen shaped to a U-shape according to one embodiment;

FIG. 39A illustrates a perspective view of an electrode lead with adistal flat portion used to interface a nerve according to oneembodiment;

FIG. 39B illustrates a perspective view of an electrode lead interfacinga nerve with a flat rectangular flap used for anchoring according to oneembodiment;

FIG. 40A illustrates a longitudinal cross-sectional view of the distalend of an electrode lead having a shapeable insert visible according toone embodiment;

FIG. 40B schematically illustrates a partial longitudinal crosssectional view of a shapeable lead assembly according to one embodiment;

FIG. 40C schematically illustrates one embodiment of a lead assembly;

FIG. 40D illustrates a longitudinal cross-sectional view of a distal endof a lead assembly in accordance with one embodiment;

FIG. 40E illustrates a longitudinal cross-sectional view of a proximalend of the lead assembly of FIG. 40D;

FIG. 41 illustrates a profile view of an electrode lead having twodistinct regions according to one embodiment;

FIG. 42A illustrates an axial view of a multi-lumen lead housingaccording to one embodiment;

FIG. 42B illustrates a perspective view of a multi-lumen lead housingshowing both shapeable insert and wires within the lumens according toone embodiment;

FIG. 43 illustrates a profile view of an electrode lead comprising agroove suitable for handling with forceps according to one embodiment;

FIG. 44A illustrates a profile view of the proximal end of an electrodelead having concentric ring contacts according to one embodiment;

FIG. 44B illustrates a profile view of an insertion tool being drawnover the proximal end of an electrode lead having concentric ringcontacts according to one embodiment;

FIG. 44C illustrates a perspective view of the proximal end of anelectrode lead having concentric ring contacts and a keyed grooveaccording to one embodiment;

FIG. 45 illustrates a profile view of an electrode lead having anindicator for a validation condition according to one embodiment;

FIG. 46A illustrates a perspective view of an electrode lead with abioadhesive tape used for anchoring proximal to conductive elementsaccording to one embodiment;

FIG. 46B illustrates a perspective view of an electrode lead with abioadhesive tape used for anchoring between conductive element accordingto one embodiment;

FIG. 47 illustrates a perspective view of a bioadhesive dispensingdevice and a light-based curing device according to one embodiment;

FIG. 48A illustrates a perspective view of a bioadhesive dispensingdevice comprising a light source and a smaller illumination area at thedistal end of the dispensing device according to one embodiment;

FIG. 48B illustrates a perspective view of a bioadhesive dispensingdevice comprising a light source and a larger illumination area at thedistal end of the dispensing device according to one embodiment;

FIG. 48C illustrates a perspective view of a bioadhesive dispensingdevice comprising a light source dispensing bioadhesive to anchor anelectrode lead to a nerve according to one embodiment;

FIG. 49A illustrates a longitudinal view of an electrode lead with aperfusion aperture used for dispensing bioadhesive according to oneembodiment; and

FIG. 49B illustrates a longitudinal view of an electrode lead withmultiple perfusion apertures used for dispensing bioadhesive accordingto one embodiment.

DETAILED DESCRIPTION

The devices, systems and associated methods described herein may be usedduring surgical procedures to locate nerve tissue, test nerve tissueexcitability and/or provide neuroregenerative therapy (e.g., electricalstimulation) to treat targeted nerve tissue (e.g., injured nervetissue). The embodiments disclosed herein can be used for peripheralnerves; however, other types of nerves can also be targeted, such as,for example, nerves in the autonomic system or nerves in the centralnervous system. For example, peripheral nerves may include the mediannerve in the upper limb, the sciatic nerve in the lower limb, smallernerves (e.g., the intercostal branches in the thorax), etc. Autonomicnerves may include, without limitation, the vagus nerve. Nerves in thecentral nervous system may reside in the spinal cord or brain.

According to some embodiments, the systems and methods disclosed hereinare configured to provide a targeted approach to both treating injuredtissue and reducing neuropathic pain with electrical stimulation byenhancing tissue reinnervation.

In some embodiments, the systems described herein may deliver one ormore bouts of neuroregenerative therapy and separate pain managementtherapy. In other arrangements, multiple bouts of neuroregenerativetherapy may be delivered that lead to enhanced tissue reinnervation. Insuch embodiments, a diminished potential for developing chronic pain orother long-term pain can result for a patient or other subject whileapplying pain management waveforms may reduce short-term acute pain.

In some embodiments, a system (and corresponding method) configured todeliver targeted electrical stimulation therapy to injured nerves isamenable to fit the needs of different injuries and clinical workflows,including different anatomical areas, injured nerves, nerve diameters,and types of nerve injury. The system can advantageously provide userswith the ability to seamlessly interchange nerve interfaces to connectwith and deliver neuroregenerative therapy (e.g., forneuroregeneration). The embodiments disclosed herein provide flexibilityto users to apply neuroregenerative therapy prior to surgery, at thetime of surgery, post-surgery, or a combination thereof, as desired orrequired. The delivery of neuroregenerative therapy can occur before,during or after the delivery of pain management therapy, as desired orrequired.

Additionally, the systems and methods allow for confirmation that thestimulating electrodes are functioning correctly by providing a means toverify the integrity of the electrode and/or system either through aphysical self-verification or automatic verification steps. This becomesadvantageous in situations where motor nerves are transected and nophysical response (e.g., no muscle contraction) is present or insituations where a pure sensory nerve is transected and there are nophysical responses from the start. This same verification method allowsfor safe and continuous delivery of neuroregenerative therapy bymonitoring current flow through the electrodes.

In some embodiments, the systems and methods disclosed herein furtherallow users to perform nerve location tasks using the same or differentnerve interfaces prior to commencing neuroregenerative therapy. Thesystem is also configured to incorporate a single button that controlsstimulus parameters, system modes, and therapy time providing an easy touse interface for a clinician minimizing training and complexity.

There exists a need for a purposely designed system that can accommodatean appropriate nerve interface for prolonged stimulation and deliverelectrical stimulation to injured nerves to accelerate nerveregeneration. Many medical disciplines can benefit from using thedisclosed system and interface to accelerate nerve regeneration. Thesedisciplines include but are not limited to: plastic surgery, orthopedicsurgery, otolaryngology, oral surgery, and neurosurgery. In addition,clinical diagnoses that would be improved from using the discloseddevice include but are not limited to: sharp lacerations, nervetransection, nerve compression, compressive neuropathy, cancer injury tonerve, peripheral neuropathy, iatrogenic nerve injury, obstetricalbrachial plexus palsy, neonatal brachial plexus palsy, facial paralysis,and radiculopathy.

More specifically, the disclosed system and interface is designed forintra-operative use and/or peri-operative use, and may improve surgicaloutcomes in the following situations: nerve transection, nervedecompression, nerve transfer, nerve graft, neurolysis, nerve allograft,thoracic outlet decompression, carpal tunnel release, cubital tunnelrelease, and tarsal tunnel release. While these listed examples maybenefit from the disclosed device, the list is not exhaustive and onlyprovides an example of what medical conditions may be treated.

Additionally, following one or more of the above listed nerve injuries,patients may experience pain following incomplete or impaired nerveregeneration. Pain may present as allodynia or hyperalgesia along theinjured nerves pathway and distally connected tissues. The disclosedsystem and methods may be used to provide pain management therapy tothese injured nerves.

In some arrangements, during the course of certain surgical procedures(e.g., complex or complicated surgical procedures), nerves may not bevisible and/or may be surrounded by connective tissue, scar tissueand/or other type of tissue. Devices such as nerve locators can be usedto probe tissue using electrical stimuli to test and confirm if thetissue is a nerve. Furthermore, there are instances where a nervelocator is used to test for motor components of a nerve fascicle priorto a nerve transfer procedure.

In some embodiments, a nerve may be transected or cut (e.g., partiallytransected, mostly transected, fully transected, etc.), crushed and/orotherwise injured or damaged. In such instances, the injured nerve(s)may benefit from application of stimulation therapy. For example, insome embodiments, brief but continuous electrical stimulation applied tothe proximal segments of the injured nerves can provide therapy and/orother benefits to the targeted nerve(s). In some embodiments, such atreatment can accelerate nerve regeneration of injured nerves. Thistreatment is referred to herein as neuroregenerative therapy.

In some embodiments, the application of a single bout ofneuroregenerative therapy may lead to enhanced tissue reinnervation thatultimately results in, among other benefits and advantages, a diminishedpotential for developing chronic pain for a patient, a decrease inresidual sensory abnormalities and an increase in fine motor skill.

In some arrangements, multiple bouts of neuroregenerative therapy maylead to enhanced tissue reinnervation, which ultimately can result in,among other benefits and advantages, a diminished potential fordeveloping chronic pain for a patient, a decrease in residual sensoryabnormalities, and an increase in fine motor skill.

The various embodiments disclosed herein offer one or more advantages.For example, the devices and systems described herein provide theability to function as a hand-held, dual-purpose technology that isdesigned and otherwise configured to deliver both nerve location/testingfunctionality, neuroregenerative therapy (e.g., continuous stimulation,intermittent stimulation, etc.) for the treatment of injured nerves(e.g., neuroregeneration), and pain management therapy. An additionaladvantage of the described embodiments is the ability to switch betweenbipolar and monopolar stimulation nerve probes as well as other probesor electrodes that can be interfaced with the system.

In some embodiments, the surgeon or other practitioner benefits by usingthe various devices, systems and/or methods disclosed hereon. Forexample, the various embodiments disclosed herein can be fullyintegrated, can replace multiple (e.g., two or more, separate, etc.)devices and/or systems, can be controlled using a single hand and/or canprovide one or more benefits or advantages.

Another benefit provided by one or more of the embodiments discussedherein is that the disclosed devices/system may apply continuousstimulation for a pre-defined period of time allowing the system to beused hands free (e.g., without the need to manipulate or otherwise use abutton or other controller to deliver stimulating energy) when used totreat injured tissue.

General System Overview

In one embodiment, the system comprises of a housing, a nerve probe, aport for additional electrodes, visual indicators, a power source, astimulus pulse generator/controller, a central processing unit, and usercontrols. With specific reference to the schematic of FIG. 1, the system100 can be configured to function in multiple configurations. Additionalconfigurations of the system may also exist, even though notspecifically illustrated in FIG. 1 and/or other figures of the presentdisclosure. For any of the embodiments disclosed herein, a device orsystem can include fewer components and/or features, as desired orrequired. For example, in some arrangements, a device or system does notinclude a visual indicator, a power source and/or the like.

In one configuration, the nerve probe 102 is bi-polar, that is,comprising two separate electrode conductors that are internallyconnected to a stimulus generator. In another configuration, as alsoillustrated in FIG. 1, the nerve probe may be bi-polar, that iscomprising two separate electrode conductors. However, in theillustrated arrangement, the conductors 104 can be shorted togetherinternally essentially producing a single probe. This connected probemay function in some embodiments as a monopolar probe if an appropriatereturn electrode is connected to the system's electrode port 106. Asshown schematically in FIG. 1, the return electrode 108 can comprise aneedle, surface pad and/or another conductive material so long as areturn path is present. Additional details regarding such embodimentsare provided herein.

In the configurations discussed above, the system 100 may be used toprobe nerve tissue with a stimulus being delivered at or near the nerveprobe. Thus, the system 100 can be used as a nerve locator or evaluator.The bi-polar or monopolar configurations may be advantageous to surgeonsdepending on the location of the nerve that is being probed or the typeof surgical procedure being performed.

In yet another configuration, such as in the embodiment also shown inFIG. 1, a cuff-type electrode 110 that is configured to interface (e.g.,directly, indirectly, etc.) with a nerve may be connected to thesystem's electrode port. Such an embodiment can be advantageous fordelivering neuroregenerative therapy to an injured nerve. In such aconfiguration, the stimulus output may be driven (e.g., entirely) to theplugged-in electrode and not the nerve probe.

In some embodiments, the electrode that is plugged into the port maycomprise of one or more electrode contacts, and through the electrodeport, may be physically connected to the stimulus generator. Regardlessof the exact configuration used, in some embodiments of the presentapplication, the system can be configured to detect if and whichelectrode is plugged into the port and ensure the appropriatestimulation is output is being driven. Additional details about varioussystem embodiments, components, portions, subsystems and/or the like areprovided below.

Housing

In some embodiments, as illustrated in FIG. 2A, the system can comprisea housing 114 that may include user controls 116, visual indicators 118,a power source, a stimulus pulse generator/controller, a centralprocessing unit and/or any other component or portion, as desired orrequired. As shown, the housing can include one or more materials, suchas, for example, thermoplastic type material (e.g., polyethylene,polypropylene, polyvinyl chloride, polystyrene, polyamides, polyesters,polyurethanes, etc.), thermoplastic elastomers (e.g., in someembodiments resulting in a soft grip-able texture), metals or alloys(e.g., stainless steel, aluminum, other brushed or polished metals oralloys, etc.), composite materials and/or the like, as desired orrequired.

In some embodiments, the housing and accompanying internal componentscan be configured to be reused. Thus, such components or portions can bedesigned and otherwise configured to be sterilized and/or otherwisecleaned. For example, the system can be sterilized via exposure toethylene oxide, chlorine dioxide, vaporized hydrogen peroxide, gammarays, electron beams and/or the like.

According to some embodiments, the housing is designed to fitergonomically into the hand of a surgeon, as illustrated in FIG. 2B.Thus, in some arrangements, the housing is shaped with grooves orscallops 120 and/or the housing includes an ergonomic shape tofacilitate holding regardless of the handedness (e.g., right-handednessor left-handedness) of the user. In other embodiments, the housing isspecifically designed for a single handedness of a user (e.g.,right-handedness or left-handedness). Such grooves or scallops 120 canbe symmetrical, non-symmetrical, aligned, offset and/or otherwiseconfigured. As shown, in one embodiment, the deepest portion of thegrooves 120 may be offset from the widest portion of the housing inrange of 0.1 to 10 mm (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5,0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7,7-8, 8-9, 9-10 mm, distances between the foregoing, etc.).

In some embodiments, the grooves 120 may be along the longitudinal axis,horizontal axis, the underside of the housing, or a combination ofabove. See, for example, FIG. 2C. In some embodiments, the housingcomprises a proximal end 122 and distal end 124. The distal end 124 caninclude visual indicators 118 and a nerve probe 102 or a combinationthereof. In some embodiments, the proximal end comprises a nerve port106 that may include a nerve probe 102.

In some embodiments, the distal end and proximal end may be collinear oroffset. For example, in some arrangements, the distal end and proximalend are offset by an angle ranging from 1° to 30° (e.g., 1-2, 2-3, 3-4,4-5, 5-6, 6-7, 7-8, 7-8, 8-9, 9-10, 10-15, 15-20, 20-25, 25-30, 5-25,10-20°, angles between the foregoing ranges, etc.), resulting in anangled distal end (e.g., relative to the proximal end). In someembodiments, such an angled distal end configuration can advantageouslyfacilitate use of the device as shown, e.g., in FIG. 2C. Additionally,the angled offset can help prevent the housing from rolling (e.g., off atable, cart, other platform, etc.) if placed on a moderately inclined oruneven surface such as when a surgeon or other practitioner may setaside the housing to perform other operative tasks.

In some embodiments, the length of the housing, or the distance fromproximal to distal ends, can be 10 to 40 cm (e.g., 10-15, 15-20, 20-25,25-30, 30-35, 35-40, 15-25, 20-40 cm, lengths between the foregoingranges, etc.). In other embodiments, the length of the housing can beless than 10 cm or greater than 40 cm, as desired or required byparticular application or use. Further, the width (e.g., diameter orcross-section dimension) of the housing can be 0.5 to 3 cm (e.g., 0.5-1,1-1.5, 1.5-2, 0.5-2, 2-2.5, 2.5-3 cm widths between the foregoingranges, etc.).

In some embodiments, the proximal end of the housing comprises ahook-shaped or other curved or angled extension or an enclosed ringphysically connected to the housing. In some arrangements, the extensionmay be used to hang the housing from an IV pole, another type of hookand/or the like.

In some embodiments, the housing may include a slot or opening tofacilitate a pull-tab that interfaces with a battery. The pull-tab mayallow for separation of the battery contacts preventing powering of thesystem. This is advantageous as it, among other things, prolongs theshelf life of the system. In some embodiments, the pull-tab slot oropening is located at, in or along the proximal end of the housing andthe width of the slot may range from 5 mm to 30 mm (or the width of thehousing). The height of the slot can range from 0.1 to 2 mm (e.g.,0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9,0.9-1, 1-1.5, 1.5-2 mm, heights between the foregoing ranges, etc.).

As illustrated in FIGS. 2A to 2D, the system 100 can comprise a firstset of user operable controls 116 for adjusting the parameters of thestimulus being delivered. In some embodiments, the system is configuredto permit the user to discretely control the stimulus parameters, forexample the stimulus amplitude or pulse width, to determine thethreshold of nerve activation (e.g., threshold testing) and/or the like.This can be particularly relevant when a nerve is encompassed by scartissue and/or other tissue (e.g., and requires a relatively largestimulus current to depolarize). Dissection of the scar and/or otherobstructing tissue can result in a lower requirement for activationcurrent.

In one embodiment, the controls may include two buttons. In anotherarrangement, the first set of controls may include a slider or similarfeature or device. In yet another arrangement, the first set of controlsmay include a wheel control (e.g., a roller, a wheel, etc.). However,any other type of control (e.g., button, dial, etc.) can be incorporatedinto the device, either in lieu of or in addition a slider and/or awheel control. In some arrangements, when using the wheel control, adiscrete set of steps may allow for adjusting the stimulus amplitude.Thus, the wheel and/or any other control can be configured to be movedbetween discrete steps or positions. However, in other arrangements, thestimulus amplitude can be selected along a range of non-discrete levels(e.g., along a continuous spectrum of amplitudes). In some arrangements,the wheel may be coupled to a rotary encoder to discretize the movementof the wheel. In other arrangements, the rotary encoder may includedetents to provide tactile feedback to the user when engaging thecontrol.

According to some arrangements, the system may also include a secondaryset of user operable controls. Such secondary controls can be configuredto start, stop and/or pause the initiation or cessation of thetreatment. In one embodiment, the secondary control may be used to powerthe system on and off. In some arrangements, the secondary set ofcontrols may be placed near the first set of user operable controls. Inone embodiment, the secondary control may be part of the primary usercontrol. For example, the slider or wheel control may be coupled to aswitch such that pressing the slider or wheel control results inactivation of a momentary switch or similar. Any other type of control(e.g., button, switch, foot pedal, touchscreen, etc.) can be used.

In one embodiment, the system comprises a pull-tab control (e.g., asdescribed herein) to control power to the system. In some arrangements,the system includes a switch or button used to control power to thesystem.

According to some embodiments, as discussed in greater detail herein,the system can also comprise a nerve port 106 coupled (e.g., physicallycoupled, operatively coupled, etc.) to the housing. This can allow usersto connect (e.g., physically or operatively couple) a separate electrodeto the system. As a control, the act of plugging in or physicallyconnecting a separate electrode to the system may change the operatingmode of the system as described earlier in system configurations.

In some embodiments, shown in FIGS. 2A to 2D, the nerve port may beincluded in the proximal aspect 122 of the housing. In somearrangements, the nerve port can allow for connections parallel to thelongitudinal axis of the housing (see, e.g., FIG. 2D). In otherarrangements, the nerve port may be included such that the connectedcomponent connector is perpendicular (e.g., exactly perpendicular, orgenerally or substantially perpendicular) to the longitudinal axis ofthe housing. In one embodiment, the act of plugging in or physicallyconnecting a separate electrode to the system enables the system topower on.

To detect if an electrode is present and physically connected to thesystem, a modified jack 130 may be included with the nerve port, asdepicted in FIG. 3. For example, in some embodiments, the jack 130 cancomprise a touch-proof jack (e.g., designed according to IEC 60601). Themodified jack may include a flexible contact 132 that may be in physicalcontact with the main pin 134. However, in such an embodiment, uponintroduction of an electrode lead connector, the physical connectionbetween the flexible contact and main pin can be configured to bebroken. In some arrangements, the jack can include one or more flexiblecontacts. In other arrangements, a polarity stand-off 136 may beincluded with the jack 130 to ensure the correct polarity of the plugbeing connected. In some embodiments, a standard touch-proof jack 130with multiple pins/contacts or equivalent is used. In other embodiments,the jack or coupling 130 can be differently configured or designed(e.g., with another set of features or components), as desired orrequired.

In some embodiments, the contacts on the jack may be wired to a jackdetection circuit shown 142, such as the one illustrated in FIG. 4. Thiscircuit 142 can include a microcontroller and passive components thatmay be used to detect the status of the connection.

In one embodiment, the circuit 142 includes standard jack detectionchips 142 used in the mobile phone industry to detect headsets. Thesechips may include but are not limited to NCX8193 from NXP Semiconductorsor MAX13330 from Maxim Semiconductor. In some arrangements, the chipscan be configured to include the benefit of moisture detection, whichallows the system to prevent enabling full power or other settings ifmoisture is detected in the jack housing. This may arise, for instance,when the system is used in an intraoperative setting.

Indicators

In several embodiments, the system comprises at least one set ofindicators 118. In one embodiment, the first indicator may include a bargraph type display made by placing at least two visual emitting devices(e.g., LEDs) near one another. In some arrangements, the first indicatormay include a multi-segment (e.g., 7-segment) display, as shown in FIG.2A. The multi-segment (e.g., 7-segment) display may include more thanone digit and decimal place, as desired or required. In someembodiments, the first indicator may comprise of a liquid crystaldisplay (LCD), a plasma display, cathode ray tube display (CRT), organiclight-emitting diode display (OLED), thin-film transistor display (TFT)and/or any other type of display.

In one embodiment, the purpose of such displays or indicators is toconvey information regarding stimulus parameters, such as, for exampleand without limitation, amplitude, pulse width, frequency, duration,other time parameter and/or the like. In some arrangements, the displayis configured to provide information related to time, such as, forexample, a timer or countdown clock. Such information can be beneficialand advantageous in determining the time remaining or elapsed of atreatment application and can help guide the surgeon or otherpractitioner is conducting neuroregenerative therapy (e.g., such asbrief electrical stimulation, other type of electrical stimulation,etc.) of injured or other targeted nerve tissue. In some arrangements, acombination of stimulus parameters, time-related parameters and/or anyother data or information is displayed on the indicator. Such dataand/or information, regardless of its exact nature, can be displayed inan alternating manner, via user controlled switch and/or the like. Insome arrangements, the user can customize the type and/or manner inwhich the data and/or information is provided by the indicator (e.g.,what data/information is provided, how it is provided to the user,etc.).

By way of example, according to some arrangements, the first set ofindicators may be used to indicate power being delivered to the system.In one example, when the previously described pull-tab (or similarfeature or component) is used to control power delivery to the systemand a user pulls the tab, the first indicator may illuminate indicatingthat the system is powered.

In some embodiments, the system comprises additional indicators, asdesired or required. For example, the system can include a second (oradditional) set(s) of indicators 118 that can advantageously provide tothe practitioner or other user additional data and/or informationprovided by a first indicator (e.g., time-related data or information,stimulus parameters, etc.). In some embodiments, the system may includea third set of indicators 118. In one embodiment, the third set ofindicators 118 is located at or near the distal aspect of the housing.However, the indicator(s) of the system, regardless of how many areincluded, what data/information they are configured to provide, etc.,can be included at any location, as desired or required. By way ofexample, the third set of indicators can comprise LEDs situated in a cap126 that acts as a light pipe. Such a cap can be physically (e.g.,directly or indirectly) coupled to the housing 114. In somearrangements, the cap and light pipe may can be designed and/orotherwise configured to permit visibility from any direction, such as,for example, when viewing the housing from above, below, beside, behindand/or the like (e.g., due to the angled distal aspect).

In some embodiments, an indicator (e.g., a first, a second, a thirdindicator, etc.) can be configured to display the status of the system.For example, a first solid color can indicate the state (e.g., active orinactive) of the output. In some arrangements, the output may bephysically (e.g., directly or indirectly) connected or coupled to thenerve probe. Thus, for instance, in some arrangements, a first solidcolor may indicate if the nerve probe is active. In one specificexample, referring to the previously described system configurations, afirst solid color may indicate the nerve probe is active in either abi-polar or monopolar configuration.

In some embodiments, a set of indicators (e.g., a third set ofindicators) can be configured to flash (e.g., on/off) a first color toindicate output of a stimulus. In some arrangements, the flashing may betimed to coincide with the output of a stimulus pulse. In otherarrangements, the flashing may be asynchronous with the output of astimulus pulse. Any other type of configuration can be used to providedata and/or other information to the user via the indicators (e.g.,different textual and/or graphical representation, different alerteffects, etc.), as desired or required.

In some embodiments, the flashing is replaced with a pulsating output.In some arrangements, the pulsating output may include the ramping up ofthe light intensity from zero to a predetermined maximum and then a rampdown from the maximum to zero. In some arrangements, the pulsatingoutput starts the ramping up from a non-zero intensity value andconcludes the ramp down from the maximum to a non-zero intensity value.

In some embodiments, a visual indicator (e.g., the third set of visualindicators) can be configured to flash or pulsate to indicate an opencircuit between the stimulating electrode and the return electrode. Inone specific example, if there is no contact between the bi-polar tipsof the nerve probe, an open circuit would be indicated that may triggerthe flashing or pulsating of the visual indicator. In another specificexample, when the system is operating in the previously describedmonopolar configuration, the lack of current flow between thestimulating electrode and the return electrode may trigger the flashingor pulsating of the visual indicator. In some embodiments, the flashingof an indicator (e.g., the third indicator) with a first color may occurat stimulus settings greater than zero.

In some embodiments, flashing or pulsating of an indicator (e.g., thethird indicator) may occur with a second color. In some arrangements,the second color may be different from the first color. By way ofexample, the flashing or pulsating of the second color may indicate aclosed circuit. In one embodiment, if there is current flow contactbetween the bi-polar tips of the nerve probe, an indication of a closedcircuit would be provided, which trigger the flashing or pulsating ofthe visual indicator. In another specific example, when the system isoperating in the previously described monopolar configuration, whencurrent flow is present between the stimulating electrode and the returnelectrode, the flashing or pulsating of the visual indicator may beactivated or triggered.

In some embodiments, the system may include a fourth (or additional)set(s) of indicators 118, as desired or required for a particularapplication or use. In some arrangements, the fourth set of indicatorsmay be present next or near to the nerve port 106. In some embodiments,the fourth set of indicators may indicate the status of the nerve port106. In some arrangements, the fourth set of indicators may functionsimilarly to the third set (and/or other sets) of indicators and cancomprise of multiple colored indicators and/or similar outputs.

The indicators described above can be incorporated into any of thedevice or system embodiments described herein and may be modified asdesired or required.

Central Processing Unit

In some embodiments, any of the system configurations described hereincan be part of a smart system with various electronic features, safetymechanisms and/or the like. Details about some of such features,mechanisms and/or other properties are provided herein.

In some embodiments, a control sub-system or central processing unit ofthe system can be built in association (e.g., around) a microcontroller150. In some arrangements, the microcontroller is configured to beprogrammed, to store and execute code and/or otherwise carry out certaintasks to property and effectively operate the system. In someembodiments, the microcontroller contains timing features, e.g.,enabling a timed stimulus output. In other embodiments, themicrocontroller interfaces with at least one or more sub-systems 152that are described herein (see, e.g., FIG. 5).

Power Source

In some embodiments, any of the systems disclosed herein can be designedto be relatively small, to be disposable, to include handheld operationand/or to include other desired or required features. In otherarrangements, the system may be reusable.

In some embodiments, the system is powered or electrically energizedusing an energy source, such as a battery, an AC source and/or the like.In some arrangements, the power source comprises a battery with astandard lithium coin cell. In other arrangements, however, if a largercapacity is needed, type N batteries or other similar alkaline batteriesmay be substituted. In some arrangements, the battery may berechargeable. Any other type of battery or other local power source canbe used, as desired or required.

In some embodiments, the system may include a power managementsub-system. In these embodiments, the power management sub-system mayinclude one or more sub-components, such as, for example, a low-noiselow-dropout switching type regulators to maintain stable operatingvoltages in the range of 3 to 5 V. For example, in some embodiments aTexas Instruments LP5912 can be used.

In some embodiments, the power-management sub-system comprises a secondsub-component having a means to generate higher voltages required tostimulate tissue. In such embodiments, the power management sub-systemcan include a low-power step-up boost converter, such as, by way ofexample and without limitation, a Texas Instruments TPS61096A. In someembodiments, the higher voltage range may be between 10 and 50 V (e.g.,10-15-15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 20-40, 25-35 V,values between the foregoing, etc.).

In some embodiments, the sub-components of the power managementsub-system are regulated (e.g., enabled and disabled) via amicrocontroller 150. In other arrangements, the act of physicallyconnecting or plugging in an electrode into the nerve port 106 mayenable or disable the sub-components of the power management sub-systemvia the jack detection circuitry 142 that was described herein.

In some embodiments, the power management sub-system may include a tiltsensor. Such a tilt sensor can be configured to provide data and/orother information to the user. For example, data or information canrelate to whether the system was placed on a flat surface or is beingheld in a non-horizontal position. In some arrangements, the output ofthe tilt sensor may engage a low power mode through the power managementsub-system.

Output Stage

In some embodiments, the system comprises a stimulus output stagesub-system. In some arrangements, the electrical output of such asub-system is configured to selectively stimulate tissue. The systemmicrocontroller can be configured to generate a rectangular stimuluspulse that is conditioned by the stimulus output stage sub-system. Thestimulus output stage sub-system can be configured to generate thestimulus pulse. In some embodiments, the stimulus pulse comprises of abiphasic constant current or voltage pulse.

In some embodiments, the stimulus output stage sub-system comprises acapacitively-coupled output, e.g., to help ensure that a net-zero chargeis being delivered to the tissue. In some embodiments, the stimulusoutput stage sub-system comprises a H-bridge used to switch currentpolarity. The H-bridge can be coupled to a current source, as desired orrequired. In some embodiments, the current source comprises a Howlandcurrent pump.

According to some embodiments, the stimulus output stage sub-system isconfigured to generate stimulus pulses with pulse durations ranging from1 to 500 microseconds (e.g., 1-5, 5-10, 10-20, 20-30, 30-40, 40-50,50-60, 60-70-70-80, 80-90-100, 100-120-120-140, 140-160, 160-180,180-200, 200-250, 250- 300, 300-350, 350-400, 400-450, 450-500, 0-20,1-30, 0-40, 0-50, 0-100, 50-150, 100-200, 100-300 microseconds,durations between the foregoing ranges, etc.). In some arrangements, thesub-system is configured to generate stimulus pulses amplitudes rangingfrom 0-20 mA (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10,10-15, 15-20 mA, values between the foregoing, etc.). In somearrangements, the sub-system is configured to generate pulse trains inthe frequency range of 0.1-100 Hz (e.g., 0.1-0.5, 0.5-1, 1-2, 2-3, 3-4,4-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 50-60, 60-70,70-80, 80-90, 90-100, 20-80-40-60, 10-70 Hz, frequencies between theforegoing, etc.).

According to some embodiments, the pulse train 154 comprises one or morepulses at an amplitude A separated by a short inter-pulse interval,called a doublet pulse 156, in the range of 1-10 ms (e.g., 1-2, 2-3,3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10 ms, intervals between the foregoing,etc.). One embodiment of such a configuration is illustratedschematically in FIG. 6A. In some embodiments, use of doublet pulsesallows exploitation of a muscle's natural catch like property resultingin greater muscle contraction or visible response.

In some embodiments, the doublet pulses 156 may be charge balancedindividually, that is, each doublet pulse may be followed by a chargerecovery pulse 158 that is equal duration but opposite polarity. See,e.g., FIG. 6B. In other arrangements, the doublet pulse may be chargedbalanced as a whole, such that a charge recovery pulse 158 that is equalin duration to the sum of the individual doublet pulse 156 durations.See, e.g., FIG. 6C. In other arrangements, the charge recovery pulse maybe generated passively by AC coupling the stimulator output. Such anembodiment produces exponentially decaying charge recovery pulses 158that are followed by each output pulse (e.g., each doublet pulse mayinclude a passively generated charge recovery pulse), as shown in FIG.6D. In some embodiments, the sub-system generates stimulus pulses,amplitudes, and/or trains sufficient to depolarize nerve fibers andelicit action potentials.

Safety Mechanisms

To ensure patient safety, in some embodiments, electrical energy is onlydelivered to the stimulating electrode or nerve probe 106 that is incontact with neural tissue when the impedance is less than 10 kOhm(e.g., less than 10 kOhm, less than 9 kOhm, less than 8 kOhm, less than7 kOhm, less than 6 kOhm, less than 5 kOhm, less than 4 kOhm, less than3 kOhm, less than 2 kOhm, less than 1 kOhm, etc.). In some embodiments,electrical energy is only delivered to the stimulating electrode ornerve probe 106 that is in contact with neural tissue when the impedanceis between 0 and 10 kOhm (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8,8-9, 9-10 KOhm, impedances between the foregoing ranges, etc.).

In some embodiments, a system according to any of the configurationsdisclosed herein includes an impedance measurement sub-system. Such asub-system can comprise a circuit that generates a sin-wave with saidcircuit coupled to a constant current source and further coupled to aset of electrodes. In some embodiments, the constant current source maycomprise of a Howland current pump.

In some embodiments, the sin wave is generated using a microcontroller'sdigital to analog converter. In other arrangements, a microcontroller'spulse-width modulation output is used and coupled to a low-pass filter.In some arrangements, the low-pass filter comprises passive components,while in other arrangements the filter comprises active components(e.g., an active filter).

In some embodiments, the impedance measurement sub-system includes aninstrumentation amplifier coupled to the electrode path used to measureimpedance. Impedance measurement can be calculated within the sub-systemand sent (e.g., digitally) to the microcontroller. In otherarrangements, the microcontroller samples the analog impedance value andconverts the value to a digital representation internally.

In some embodiments, when an electrode is properly placed in contactwith neural tissue, the electrode-tissue impedance will be smaller thanthe impedance when the electrode is not in contact with tissue. In somearrangements, the impedance is such circumstance is typically less than10 kOhm (e.g., 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 3-8,1-10, 4-8 KOhm, impedances between the foregoing ranges, etc.). Suchlower resistance can exist because healthy, internal human tissueprovides a relatively low resistance electrical pathway through whichelectrical current may pass. In some embodiments, resistances exceedinga threshold value (e.g., 10 kOhm) can be an indication of improperplacement of the electrode. In some arrangements, the system isconfigured of recognizing values exceeding such a threshold.

In some embodiments, the system is configured to periodically detect theimpedance during the continuous application of electrical stimulation.In some arrangements, if relatively high impedance is detected (e.g.,high compared to a threshold level or upper limit), the system can bedesigned and otherwise configured to pause the application of continuouselectrical stimulation and enable an indicator 118 on the housing 114 toalert the operator. In other arrangements, the system is configured toterminate (e.g., automatically stop) the stimulus output and/or promptthe user. In some embodiments, the indicator comprises a visualindicator; however, in other embodiments, the indicator can include anauditory indicator and/or any other type of indicator, either inaddition to or in lieu of visual indication.

As noted herein, to further enhance patient safety, in some embodiments,the output of the system is capacitively coupled to prevent net DCcharge inflow into the electrode tissue interface.

Nerve Probe and Electrodes

A nerve probe 102 can be used to probe tissue to test for excitability.Bodily tissues such as nerves may conduct action potentials towards amuscle when probed using physical means, electrical stimulation and/orthe like resulting in a muscle twitch, reflex or contraction. Accordingto some embodiments, the devices and systems disclosed herein include anerve probe physically coupled to the housing and electrically coupledto the stimulus output stage sub-system.

In some embodiments, the nerve probe comprises a single conductiveelement in the shape of a cylinder or rod that extends from thehousing's distal end. In other embodiments, the shape of conductiveelement can vary. In some arrangements, the nerve probe is entirely (ornearly entirely) electrically insulated except for a small de-insulatedcomponent on the distal aspect of the nerve probe. For example, themajority of the nerve probe is electrically insulated (e.g., over 70%,70-100%, 80-95%, etc.). The area of de-insulation can range from 0.1 mm²to 10 mm² (e.g., 0.1-0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9,9-10, 2-8, 1-9, 4-8 mm², areas within the foregoing ranges, etc.). Insome embodiments, the insulation may be manually configured tode-insulate the probe by a varying percentage, such as, for example1-30% (e.g., 1-2, 2-3, 3-4, 4-5, 5-10, 10-15, 15-20, 20-25, 25-30%,percentages within the foregoing ranges, etc.).

In some arrangements, the single conductive element functions as acathode or stimulating electrode. In such an arrangement, an appropriatereturn path for current to flow is necessary. In some embodiments, thereturn path may be provided by connecting a return electrode to thenerve port 106. The return electrode can comprise a needle, a surfacepad, another conductive element and/or the like.

In some embodiments, the nerve probe comprises a plurality of conductiveelements. In some arrangements, one or more of the conductive elementscan be designed and otherwise configured to function as a returnelectrode or anode, while one or more of the conductive elements can bedesigned and otherwise configured to function as cathodes or stimulatingelectrodes.

In some embodiments, the conductive elements comprise one or more metalsor alloys (e.g., stainless steel, platinum, iridium, gold, etc.). In onearrangement, the conductive elements comprise platinum or 90/10 platinumiridium, gold. The conductive elements can comprise any other conductivemetal, alloy and/or other material, as desired or required.

In some embodiments, the length of the conductive elements is 0.5 to 10cm (e.g., 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 3-7,5-10, 0-5 cm, lengths within the foregoing ranges, etc.). However, thelength of the conductive elements can be greater than 10 cm to meet therequirements of a particular application or use. The diameter or othercross-sectional dimension of the conductive elements can be 0.1 to 5 mm(e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5,0.1-2, 1-2 mm, values within the foregoing ranges, etc.). However, thediameter (or other cross-sectional dimension) of the conductive elementscan be greater than 5 mm and/or to meet the requirements of a particularapplication or use.

In some embodiments, the system does not include a nerve probe. Instead,for such configurations, the system can rely on an appropriate electrodeapparatus to be connected to the nerve port. In some arrangements, theelectrode apparatus comprises monopolar or bipolar catheter typeapparatus. Such arrangements can be particularly advantageous inperi-operative scenarios where the lead may be placed intraoperativelyand, due to its shape, may be easily removed from a closed incision orpercutaneous access point.

In some embodiments, a nerve cuff electrode apparatus is connected tothe nerve port. A cuff electrode can be particularly advantageous inintraoperative settings where a dissected nerve is easily accessible.However, as discussed herein, for any embodiments disclosed in thisapplication, the electrode can include a configuration other than a cuffelectrode.

Certain embodiments of a nerve cuff electrode apparatus 10 areillustrated in FIGS. 7 to 11. As shown, the nerve cuff electrodeapparatus 10 can comprise a carrier body 12. In some embodiments, thecarrier body 12 and/or other portions of the apparatus 10 comprise oneor more insulative materials, such as, for example, silicone rubber,other elastomeric and/or polymeric materials and/or any other materials.One or more materials can be used, either in lieu of or in addition torubber, such as, for example and without limitation, thermoplasticelastomers, elastomeric polyurethanes and/or the like. In someembodiments, the material(s) included in the apparatus are flexible soas to permit bending without breaking, fracturing and/or other damagebrought about by movement during use.

In some embodiments, the electrode apparatus 10 is arranged in alongitudinal manner with the length being considerably longer than thewidth. For example, in some embodiments, the ratio of the length towidth of the electrode apparatus 10 can be between 1:1 to 20:1 (e.g.,2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 20:1, ratios withinthe foregoing ranges, etc.). In some embodiments, electrode apparatus 10comprises two ends, a head portion 16 and a tail portion 26.

As shown in FIG. 7A, the apparatus 10 can include a longitudinal axis 11that extends longitudinally or length-wise along the apparatus 10. Thelength of the device can be 20 to 80 mm. The width of the apparatus 10(e.g., the dimension perpendicular to the longitudinal axis 11) can be 5to 30 mm. Thus, in some embodiments, the length of the apparatus 10 is 2to 5 times the width of the apparatus. However, in other arrangements,the width can be equal or greater than the length. In some embodiments,the thickness of the head portion 16 can be 1.5 mm. In somearrangements, the thickness can range from 0.1 mm to 5 mm (e.g.,0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9,0.9-1, 1-2, 2-3, 3-4, 4-5 mm, thicknesses within the foregoing ranges,etc.), as desired or required.

The head portion can contain a tapered end 16 that is rounded andcontains gripping structures 18 that aid a surgeon in handling theelectrode apparatus. In some embodiments, the gripping structures 18 arepresent on either side of the tapered end of the carrier. However, inother embodiments, gripping structures 18 are included only on one side.In some embodiments, the gripping structures 18 include ridges,recesses, protrusions and/or the like. In some embodiments, suchstructures 18 are formed into the surface or body of the apparatus, andthus, form a unitary structure with the portion in which they areincluded. For example, the ridges or other structures 18 can be molded(e.g., injected molded) together with the main portion of the apparatus.However, in other arrangements, the gripping structures 18 are separatefrom the main portion of the apparatus and/or are created after the mainportion of the apparatus is formed (e.g., via one or more connectionstechnologies or methods, by removal of material, etc.). In someembodiments, the gripping structures are replaced by a through-hole ormultiple holes where one or more sutures can be threaded.

With continued reference to FIG. 7A, the tail portion 26 of theapparatus 10 can be non-tapered. However, in other configurations, atleast a portion of the tail portion 26 is tapered, as desired orrequired. In some embodiments, the tail portion 26 comprises rounded orcurved corners to facilitate handling of the apparatus. In someembodiments, the tail portion comprise one or more areas that aresubstantially thicker than the head portion to encompass a through-holein the longitudinal axis 11 that allows for placement of electrode leadwires. In some embodiments, the thicker area can be greater than 1 timesthicker than the head portion (e.g., 1 to 5, 1 to 10, 1 to 20 timesthicker, etc.), but not thicker than the grooved body 24. In someembodiments, the thickening of the tail portion may be in the oppositedirection from the thickening of the grooved body 24 and can alsoinclude a through-hole in a diagonal direction from the bottom face ofthe tail portion to the midbody to allow accommodation of an electrodelead wire.

As shown in FIG. 7A, the mid portion of the carrier can include twofeatures: a grooved body 24 and a winged locking mechanism 20. Thegrooved body 24 can be structured and configured so that when a surgeonplaces a nerve on the electrode apparatus 10, the nerves longitudinalaxis is perpendicular (e.g., substantially perpendicular) to theelectrode's longitudinal axis 11, with the nerve itself naturallysettling in the thinner mid-portion 28 of the grooved body, in someembodiments.

In some embodiments, the winged locking mechanism may be positioned invarious locations longitudinally and may include more than one set(e.g., 2 wings) at each location. In some embodiments, the locking wingsare positioned in a staggered arrangement.

The thinner mid-portion 28 of the grooved body 24 can be shaped tofacilitate placement of a nerve and to wrap or bend the head portion 16of the apparatus around (e.g., at least partially around) the nerve. Interms of nerve placement, in some embodiments, the thinner mid-portion28 follows the shape of a semi-circle or other circular or curved shape.This can help prevent the nerve tissue from sliding off the electrodeapparatus 10. The radius of curvature of the thinner mid-portion 28 canrange from 1 to 10 mm (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9,9-10, 2-8, 4-8, 5-10 mm, radii within the foregoing ranges, etc.). Insome arrangements, the radius of curvature is greater than 10 mm (e.g.,10-15, 15-20, 10-20, 10-50 mm, radii between the foregoing, greater than50 mm, greater than 100 mm, etc.), as desired or required.

In some embodiments, the thinner mid-portion 28 of the grooved body 24is flat and tangent to the head portion 16 of the electrode apparatus10. The thickness of the mid-portion can range from 0.1 mm to 5 mm. Insome arrangements, such as the desired curved shape described above, thethinnest section can be 0.1 mm (e.g., 0.05 mm to 2 mm). In someembodiments, the thinnest section can be 10% (e.g., 5-25%) of thethickest section of the head portion 16 of the electrode apparatus 10.The thickness of the mid-portion 28 can be designed and otherwiseconfigured to adjust for how flexible the apparatus is when the headportion 16 is wrapped around a nerve.

In some embodiments, the grooved body 24 of the mid portion 28 comprisesof a uniform or a generally uniform thickness. That is, the mid portionis of similar thickness as the connected head portion 16, providing aflat plane. In some arrangements, the carrier may include electrodesplaced on the underside of the carrier 12. In some embodiments, thelocking mechanisms may be engaged in a reverse orientation such thatwhen carrier is folded, the head portion 16 engages the lockingmechanism from the direction of the tail portion.

In some arrangements, the desired curved shape described herein followsthe shape of a semi-circle or other partially rounded or curved shapewith a uniform thickness to that of the head portion 16. In somearrangements, the base of the semi-circular groove can protrude, atleast partially, below the plane of the head portion 16 to create alarger circumference for nerve placement.

In some embodiments, the groove also contains one or more conductiveelectrodes 30 that may be present in various configurations as outlinedfurther below. In some arrangements, the purpose of the groove is tofacilitate interfacing with a nerve while preventing or limitingslippage of the nerve. Such a configuration can also, in someembodiments, facilitate contact between the nerve and the conductiveelectrode(s) 30. Once the nerve is in place, the surgeon or otherpractitioner can grasp the tapered head portion 16 of the carrier (e.g.,using either forceps, his/her fingers, other devices or methods, etc.)and can wrap (e.g., at least partially) the nerve. In some embodiments,to lock the cuff in place, the tapered head portion 16 is placedunderneath the winged locking mechanism 20. Since the electrodeapparatus can advantageously be configured to accommodate differentdiameter nerves or nerve bundles, the surgeon or other practitioner canapply as much or as little wrapping pressure to sufficiently cover thenerve. To securely lock the tapered head portion 16, the surgeon canlaterally deflect the winged locking tabs 22 and place the tapered headportion 16 underneath them and then release the tabs.

In one embodiment, the carrier is molded in a flattened or openedposition. For example, the carrier can be bent and placed underneath thelocking tabs 22. In some embodiments, a natural bias force exists thatpresses or otherwise urges the tapered head portion 16 against thelocking tabs 22 preventing the tapered portion from sliding further downthe longitudinal axis 11 of the apparatus and potentially compressingthe interfaced nerve.

In some arrangements, when a surgeon or other practitioner is finishedusing the electrode apparatus 10, he or she can laterally deflect thelocking tabs 22, and the tapered head portion 16 of the carrier can beconfigured to spring back due to the bias force pushing back to itsoriginal flat or open conformation. Such a feature can allow for quickrelease of the interfaced nerve. Accordingly, the surgeon or otherpractitioner can then pull the nerve cuff from the tail end 26 and slideit from beneath the interfaced nerve without damaging it.

With continued reference to FIG. 7A, a single conductive electrode pad30 is placed on the grooved portion of the carrier 24. In somearrangements, this is the thickest portion of the carrier and serves oneor more purposes (e.g., to provide an insulative barrier to preventcurrent spread, to provide stiffness to reduce the probability ofelectrode pad delamination during the time it is flexed around the nerveand then released, etc.).

In some embodiments, the electrode pad 30 comprises a monopolar singlecontact configuration. A lead wire 32 can be coupled to the electrodepad 30 (e.g., via laser or resistance welding, crimping, using othertechnologies or techniques, etc.). In some embodiments, a physicalconductive connection is made with the electrode pad. FIG. 7Billustrates a cross-sectional view through a midplane of the electrodeapparatus 10. As shown, an electrode pad 30 is coupled to a lead wire32. The tail end of the lead 36 can be externalized from the electrodeapparatus.

According to some embodiments, as shown in FIG. 8A, the tail end of thelead 36 exits the apparatus from the tail end of the carrier 26,parallel or generally parallel to the longitudinal axis of the carrier.In some arrangements, when interfaced with a nerve 14 (see FIG. 8B), theapparatus 10 with secured head portion 16 using the winged lockingmechanism 20 has the lead wire positioned conveniently away from thenerve. Accidental pulling or movement of the lead wire can move theinterfaced nerve 14 in a direction close to perpendicular to itslongitudinal axis. In another embodiment, as shown in FIG. 8C, the tailend of the lead wire 36 can exit perpendicular to the longitudinal axis11 of the carrier 12.

In some arrangements, as shown in FIG. 9A, the electrode pad 30 and leadwire 32 are connected to the carrier via a through-hole 40. In someembodiments, the through-hole is cut or otherwise created in a thickenedportion 42 of the tail end of the carrier 26. In some embodiments, asdepicted in FIG. 9B, the through-hole can be a straight line from thetail end of the carrier 26 and can exit through a hole or other opening46 of the grooved body 24.

In some embodiments, the through-hole containing lead wire 32 comprisesone or more through-holes with the angle between their longitudinal axisvarying. Such a configuration can result in a chamber where a lead wire32 can be placed similar to what is shown in FIG. 7B. In somearrangements, the longitudinal axes of the through-holes are angled at45 degrees (e.g., 30-60 degrees) to one another. In some arrangements,such an angle is between 0 and 90 degrees (0-10-10-20, 20-30, 30-40,40-50, 50-60, 60-70, 70-80, 80-90, 45-90, 45-60, 15-45 degrees, angleswithin the foregoing ranges, etc.), as desired or required.

In some embodiments, the electrode pad 30 is secured to the apparatusvia a secondary enlarged electrode area 34 that is substantially largerthan the through-hole in which the lead wire is inserted. In someembodiments, the electrode pad 30 is protruding relative to the adjacentportions of the apparatus. In other arrangements, the electrode pad maybe insert molded flush or recessed relative to the adjacent portions ofthe apparatus. In other arrangements, the electrode pad is secured by anenlarged secondary electrode area 34 and/or is flush or recessedrelative to the adjacent portions of the apparatus, as desired orrequired.

According to some embodiments, as illustrated in FIG. 10A, the electrodecontact pads of an electrode apparatus 10′ are not limited to a singleconductive pad. Instead, as shown, the apparatus can include two (ormore) pads placed in a bipolar configuration (e.g., in a similar mannerto the single electrode pad 30). The spacing between bipolar pads can be5 mm. In some arrangements, the spacing can range from 0.1 mm to 5 mm orfrom 0.1 mm to the width of the electrode apparatus.

For more precise or selective stimulation of axons within a nerve, atripolar electrode pad configuration may be used, as shown in theelectrode apparatus 10″ of FIG. 10B. The spacing between adjacentelectrode pads may range from 0.1 mm to 2 mm. In some arrangements, aplurality of more than three electrode pads can be introduced withcontact spacing ranging from 0.1 mm so long as the electrode pads fitinto the width of the apparatus.

In yet other embodiments, as illustrated in FIGS. 11A and 11B, electrodepads can be in the configuration of a conductive electrode strip 50 andeither printed on the carrier, glued to the carrier using adhesiveand/or disposed on the carrier using some other method or technology. Insome embodiments, the electrode pads comprise metallic foil (e.g.,platinum iridium 90/10) and arranged in a bipolar configuration (FIG.11A). In some embodiments, the metallic foil can comprise gold and/orany other conductive material, either in addition to or in lieu ofplatinum iridium, as desired or required. In some embodiments, asdepicted in FIG. 11B, a tripolar configuration of foil strips can beused. The spacing between adjacent strips can be similar to the spacingbetween electrode pads described above.

The conductive electrode strip 50 can be embedded within the carrierbody 12, as shown in FIG. 11C. In some embodiments, the carriercomprises laser cut windows or other openings 54 to at least partiallyexpose the metal contacts and permit interfacing with tissue. Accordingto some arrangements, the majority of the foil is placed within thethinner mid-portion of the grooved body 28 or grooved body 24 of thecarrier 12. This can be particularly helpful with respect to conductivestrip electrode placement, in some embodiments, to minimize or reducepotential delamination when the head portion 16 is wrapped around thenerve 14 and interfaced with the winged locking mechanism 20. Theconductive electrode strips can be configured in a variety of waysincluding an array arrangement of a plurality of electrode strips (morethan 3, e.g., 4, 5, 6, etc.), as desired or required for a particularapplication or use. In some embodiments, as discussed in greater detailherein, the electrode apparatus 10 can be used to record tissue or nerveactivity as well deliver electrical stimulation.

FIG. 12 illustrates yet another embodiment of an electrode apparatus. Asshown, the locking apparatus can include a strap 60 that allows asurgeon or other practitioner to pull the head portion 16 of the carrierbody 12 under the strap 60 (e.g., using forceps or some other tool).Such movement can permit the surgeon or other practitioner to size thecarrier body 12 to fit a nerve appropriately. As in previousembodiments, the molding of the electrode apparatus 10 in a flatconfiguration can create a biasing force (e.g., to press upwardly on thestrap when the head portion 16 of the carrier is threaded under thestrap). Such a biasing force can help prevent or reduce the likelihoodof the head portion 16 from undesirable movement. Additionally, thefriction of the elastomeric material can further prevent or reduce thelikelihood of movement of the head portion 16 of the carrier body 12while engaged with the strap 60. In some embodiments, in order to removethe electrode apparatus from the nerve, the surgeon or otherpractitioner may cut or otherwise compromise the strap 60. This canrelease the head portion 16, and the biasing force can allow theelectrode apparatus 10 to return to a flat or generally flatconformation.

In some embodiments, a conductive electrode strip 50 can be included inany of the electrode configurations disclosed herein. The strips canextend to the location of the strap 60 in one direction and to thetapered portion of the head portion 16 of the apparatus. The conductivestrips 50 can be attached or otherwise coupled to the electrode carrierbody 12 (e.g., as previously described). The electrodes may not belimited to the described strips but may also include other electrodeembodiments described previously.

In some arrangements, as shown in FIG. 13, the locking apparatusincludes one or more paired apertures 70 and one pair of correspondingprotrusions 72 or buttons with a surface protrusion (e.g., with adiameter that is larger than the aperture). The apertures can range indiameters (or other cross-sectional dimensions) from 1 to 10 mm (e.g.,1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 2-8, 4-8, 1-5, 5-10 mm,dimensions within the foregoing ranges, etc.). However, the diameters orother cross-sectional dimensions can be greater than 10 mm or smallerthan 1 mm, as desired or required for a particular application or use.The corresponding paired buttons or protrusions 72 can include a cap 74(e.g., a hemi-spherical cap) with a diameter or other cross-sectionaldimension that may be equal to or larger than the paired aperture 70. Insome embodiments, the protrusions comprise a cylindrical (or generallycylindrical) section that is attached to the carrier body 12 and may besmaller than the hemi-spherical cap 74.

In some embodiments, one or more different locking mechanisms can becombined such that the head and tail ends are fastened more securely. Insome embodiments, the head portion 16 is fastened with a wingedmechanism at a given longitudinal position and additionally fastenedwith a secondary mechanism (e.g., of the same winged mechanism or othermechanism), to provide additional locking strength in securely holdingthe head portion. The surgeon or other practitioner can determinewhether using additional locking mechanisms is necessary at the time ofuse.

In any of the embodiments disclosed herein, one or more conductiveelectrode strips 50 can be included. The strip(s) can extend to the lastpair or locking apertures 70 in one direction and to the paired buttons72 in the other direction. The conductive strips 50 can be attached tothe electrode carrier body 12 as previously described. The electrodesmay not be limited to the described strips, but may also include otherelectrode embodiments described herein, as desired or required for aparticular application or use.

In some embodiments, the carrier body 12 includes two or more sets ofwinged locking mechanisms (e.g., placed on either side of a symmetricalgroove within the carrier body). In some arrangements, the carrier bodycan comprise one or more electrodes within the groove. The carrier bodyand accompanying locking mechanisms can be configured to engage with asecond carrier body containing one or more electrodes. In someembodiments, the second carrier body is equal to or longer than thefirst carrier body. The second carrier body can be placed on top of thefirst carrier body and engage the locking mechanisms in order to securea nerve placed between both carrier bodies.

The distance between the locking mechanisms and the groove can bevariable or can be symmetrical with respect to the grooves center line.In some arrangements, the locking mechanisms include a strap or lockingapertures as described herein.

According to some embodiments, as shown in FIG. 14, an adhesive patch 80is added to the lead wire 32. This can advantageously assist tostabilize the electrode apparatus 10 and prevent (or at least reduce thelikelihood of) any inadvertent movement. By way of example, suchmovement can occur if a user accidentally pulls on the lead wire 32 orinteracts with the wire during a surgical procedure. The adhesive patch80 can be affixed (e.g., directly or indirectly) to a part of theanatomy that is close to an incision or other area being treated ortargeted.

In one embodiment, the adhesive patch 80 comprises carbon impregnatedrubber or similar elastomeric materials. The elastomeric materials usedfor the patch 80 can be impregnated with conductive elements, as desiredor required. In one embodiment, the adhesive patch 80 (e.g., one side ofpatch) can include a conductive adhesive gel (e.g. Parker Labs TensiveConductive Adhesive Gel).

The adhesive patch 80 can include a rectangular shape. For example, insome embodiments, the patch is rectangular and comprises a length of 10mm to 100 mm and a width of 5 mm to 50 mm. Thus, in some embodiments,the length of the adhesive patch 80 is 1.5 to 5 times the width of theadhesive patch 80. In one embodiment, the distance of the adhesive patch80 to the electrode apparatus 10 may range from 50 mm to 300 mm. Thesize, orientation, dimensions and/or other properties of the patch canbe different than disclosed herein. For example, in some arrangements,the shape of the patch is circular, oval, triangular, other polygonal,irregular and/or the like.

With continued reference to FIG. 14, the adhesive patch 80 can compriseone or more visual indicators 82, such as LEDs, to provide a statusindication to the user. The indicator can be powered by a connecteddevice such as an electrical stimulator or biological amplifier.

In some embodiments, the indication is configured to confirm properdelivery of stimulus pulses or high impedance of the electrode. In somearrangements, the indicator is configured to display, in the case ofneuroregenerative therapy, a timer or stimulation amplitude levels. Anyother data, information, confirmation and/or the like can be configuredto be provided to the user, as desired or required.

In some embodiments, the adhesive patch 80 comprising one or moreindicator(s) 82 (e.g., visual indicator(s)), can include a moldedsection 84 to embed the indicator. In some arrangements, the moldedsection includes additional circuitry (e.g., to power the indicator, tocontrol the indicator, to provide other non-visual cues to the end user,etc.), as needed or required.

In some embodiments, the electrode apparatus 10 that is connected to theadhesive patch 80 comprises a single electrode contact resulting in amonopolar stimulation field. In some arrangements, the adhesive patch 80can function as a return electrode for the monopolar stimulation field.

In other arrangements, as illustrated in FIG. 15A, the adhesive patch 80may connect to a monopolar electrode 180 that comprises a needle orneedle-like apparatus. The adhesive patch 80 comprises circuitry toshape and deliver stimulus pulses to a connected electrode (see, e.g.,FIG. 15B). In some arrangements, the patch and circuitry are powered byan included battery source 182. The circuitry can comprise elementssimilar to those described herein with reference to other embodimentsfor the electrical stimulation system, such as a microcontroller 150. Insome embodiments, the circuitry comprises a time (e.g., 555 timer) orsimilar device, component or feature used to generate the stimuluspulses. In the embodiments discussed above, associative passive elementscan also comprise the circuitry such as resistors 190 and capacitors192, as needed or required.

In some embodiments, the adhesive patch 80 comprising circuitry used toshape and deliver stimulus pulses, may include one or more indicators 82(e.g., visual indicators), as described in greater detail herein. Insome embodiments, the function of the adhesive patch 80 and includedcircuitry is to test the connectivity and placement of the monopolarelectrode.

In some embodiments, as illustrated in FIG. 15A, the adhesive patch 80includes a push-button 184 used to initiate or deliver one or morestimulus pulses to the electrode 180. In some arrangements, such apush-button 184 can also be configured to change the stimulus amplitudeand/or other stimulus parameters (e.g., frequency, pulse width and/orthe like), as desired or required for a particular application or use.

In some embodiments, the adhesive patch 80 may include a multi-segmentdisplay (e.g., a 7-segment display). The 7-segment or othermulti-segment display can comprise more than one digit and decimalplace, as desired or required. The display can include a liquid crystaldisplay (LCD), a plasma display, an organic light-emitting diode display(OLED), a thin-film transistor display (TFT) and/or any other type ofdisplay, as desired or required for a particular application or use. Thedisplay may provide information such as stimulus parameters, therapytime remaining, battery power levels, mode of operation, connectivitywith other devices, etc.

In some arrangements, the adhesive patch 80 comprises a connector 186used to interface with a second stimulation system. Such a connector canfunction similarly to the previously described nerve port embodiments.In some arrangements, the connector 186 comprises a molded component 188that interfaces with the adhesive patch 80 (e.g., seamlessly or nearlyseamlessly). In some embodiments, the second stimulation system includesa battery with greater capacity or any other type of system, device,component and/or the like, as desired or needed for a particularapplication or use. The second stimulation system can include elementssimilar to stimulation systems described with reference to otherembodiments herein. In some embodiments, the second stimulation systemmay be incorporated into the adhesive patch.

According to some embodiments, the circuitry present on the adhesivepatch may include elements such as switches 194 or other components orfeatures to direct the stimulus output from the first or secondstimulation system. In some embodiments, the adhesive patch comprises ofmultiple layers (see, e.g., FIG. 15C). Some of the layers in such aconfirmation can include a gelled conductive rubber layer 196, a layerincorporating electrical circuitry and other electrical elements 198, anelastomeric protective layer 200 and/or any other layers or components.

In some embodiments, as depicted in FIG. 16A, the electrode carrier body12 is coupled (e.g., directly or indirectly) via one or more small tabs90 to a polymer or microsurgical background material 92. Such a material92 can typically be used to separate or isolate a nerve or other tissuefrom surrounding tissue, allowing a surgeon or other practitioner tofocus (e.g., solely or more exclusively) on repair or dissection of theisolated tissue.

According to some embodiments, as illustrated in FIG. 16B, the carrier12 and coupled background material are used to isolate an injured nerve94 (e.g. a transected nerve) with the proximal end of the injured nerveplaced on the electrode apparatus 10. The distal end of the injurednerve 94 can be placed on the background material. If, by way of exampledepicted in FIG. 16B, a transected nerve does not require a nerve graftto bridge the distance between proximal and distal ends, the coaptationof both nerve ends can be accomplished directly on top of the backgroundmaterial. If a nerve graft is to be used to bridge the gap betweenproximal and distal ends of a transected nerve, the insertion of thenerve graft can be accomplished on the background material.

In one embodiment, prior to repair of the injured nerve 94 (e.g.,immediately prior to such repair), the electrode apparatus 10 can bedisconnected from the background material by cutting (or otherwisecompromising) the tabs 90. In some embodiments, the disconnected carrierbody 12 can then wrap or surround the injured nerve 94, as shown in FIG.16C, with wrapping of the proximal nerve stump prior to engaging thewinged locking mechanism 20, and neuroregenerative therapy (e.g.,relatively brief electrical stimulation) may be delivered to accelerateand facilitate nerve regeneration. During this time, a surgeon canperform a nerve repair or graft installment distally (e.g., immediatelydistally) to the electrode apparatus with the distal aspect of theproximal portion of the nerve and the distal transected nerve 94 beingpositioned on the background material 92.

For any of the embodiments disclosed herein, or equivalents thereof, alead wire 32 connected to the conductive electrode pads 30 can becoupled (e.g., connected) to a stimulus output sub-system. This can helpprovide stimulation pulses to depolarize axons or electrically stimulatetissue. In other embodiments, the lead wire may be connected to abiological amplifier to record signals from a nerve or other tissueand/or to any other system, subsystem, device and/or the like, asdesired or needed for a particular application, indication or use.

According to some embodiments, a percutaneous electrode lead 250 may becoupled to the adhesive patch 80. The electrode lead, as illustrated inFIG. 17A, may comprise of one or more conductive elements 252. Theconductive elements can be placed on or near the tip of the lead, asillustrated in one example in FIG. 17A. In other arrangements, theconductive elements 252 can be positioned along the length of the lead,either in lieu of or in addition to being at or near the tip of thelead, as desired or required.

In some embodiments, the electrode lead comprises a circular or curvedshape (e.g., at least a partial circular or curved shape) and comprisesan outer diameter (or other cross-sectional dimension) of 0.1 to 5 mm(e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8,0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 1-4, 0.5-4, 1-4 mm, ranges betweenthe foregoing, etc.). In some arrangements, the diameter or othercross-sectional dimension is determined (at least in part, e.g.,largely) by the lead housing 254 (e.g., the size, shape and/or othercharacteristics of the lead housing). In other embodiments, theelectrode comprises a needle.

The lead housing 254 can comprise one or more elastic or semi-elasticmaterials, such as, for example, silicone rubber (e.g., silicone rubbertube), polyurethane, other polymeric materials, other types ofelastomeric or rubber materials, other flexible or semi-flexiblematerials, etc. The lead can be placed near a nerve through an existingincision or through a percutaneous approach (e.g., where a needle orother sharp object with a cannula are utilized to provide access to thenerve). The flexibility of its materials/construction and/or similarphysical characteristics of the lead housing 254 can be selected tofacilitate for easy removal of the percutaneous electrode lead 250. Insome embodiments, the lead housing 254 comprises a lead wire 256 that isphysically connected to a conductive element 252, as illustrated, e.g.,in FIG. 17B.

In some embodiments, the lead housing can comprise of a uniform orcontinuous material thickness throughout the length of the lead. Inother embodiments, the lead housing includes areas of differentthickness that serve as bendable joints that can provide addedflexibility for shaping the lead. In some arrangements, desired shapesare retained until other forces are applied that reshape the lead, forexample manual manipulation or the act of lead removal. In otherembodiments, these joint segments may comprise of materials differentfrom the rest of the housing. In some embodiments, the joint segmentsmay be more or less flexible than the remainder of the lead housing.

In some embodiments, the lead housing may include a coiled wire that isused to provide shape memory for the lead. This can be particularlyadvantageous in areas where the lead is required to bend and maintainits shape. In some arrangements, the coiled wire spans the length of thelead. In other arrangements, the coiled wire may only span a firstlength or portion (e.g., the first 10 cm or less, such as, for example,0-10, 2-8, 1-5, 5-10 cm, lengths between the foregoing ranges, etc.) ofthe lead. However, the extent of the coiled wire need not be limited tothese distances (e.g., can be greater than 10 cm, as desired orrequired). In some embodiments, the coiled wire is physically coupled(e.g., directly or indirectly) to an electrode. In other embodiments,the coiled wire is not electrically coupled to any stimulatingelectrodes. In some embodiments, the coiled wire serves as an electricalconnector to other circuitry located at, along or near the distal end ofthe lead housing. Depending on the application, required flexibility andmemory properties and/or other design considerations, the spacingbetween adjacent coils is zero (e.g., the coils are touching oneanother) or is a fixed distance. In some embodiments, the coiled wire isinsulated or uninsulated. In some arrangements, the coiled wire isencased in flexible material such as various durometers of Pellethane®or Pebax® or similar thermoplastic polyurethanes or elastomersmaterials.

In some embodiments, the percutaneous electrode lead 250 can beconnected to an extension wire that is then connected to the stimulationunit to provide more length in cases where the stimulation unit isplaced further from the area where the electrode lead 250 is placed. Theextension wire can comprise an additional length of 30 to 100 cm (30-40,40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 50-80 cm, distances betweenthe foregoing ranges, etc.). The extension wire may be of similar ordifferent material properties with at least one end that interfaces theelectrode lead and makes electrical contact and at least one end thatinterfaces the stimulation unit and makes electrical contact. In someembodiments, when the stimulation unit, the extension wire and electrodelead are connected, they function as an integrated unit and performsimilarly as described.

In some embodiments, the electrode lead housing 254 includes fiducialand/or other markers to help indicate distance from the tip of the lead.Other markers (e.g., fiducial markers) can include radiopaque markers orhigh echogenicity markers for image guided placement of the lead. Imageguided placement of the electrode lead 250 may be advantageous insituations where direct visualization of the injured nerve and/or theelectrode lead is not possible. Such situations, for example, may arisewhen a patient is undergoing a nerve repair or decompressive procedureunder local anesthesia. Depolarization of axons is not possible withinthe region that is anaesthetized. In some embodiments, in order toprovide neuroregenerative therapy to the injured nerve, it isadvantageous to place the electrode lead 250 proximal to the region ofanesthesia. In some embodiments, for the therapy to be effective (ormore effective), the electrical field that is produced by the lead mustdepolarize the non-anesthetized proximal branches of the injured nerve.In one non-limiting example, a patient may undergo carpal tunnel releaseunder local anesthesia, a procedure that anesthetizes the wrist. In someembodiments, proximal branches of the medial nerve, such as in theforearm, are not superficial, and image-guided placement of theelectrode lead 250 would be advantageous to a surgeon in order toprecisely target the proximal component of the injured median nerve. Insome arrangements, image-guided placement also assures that blindinsertion of the lead does not result in damage to surrounding vascularstructures.

In another example, insertion of the electrode lead using image guidancemay also be advantageous in situations where a nerve repair or othersurgery may have been performed previously but the patient did notreceive electrical stimulation therapy at time of the original repairprocedure. In such situations, placement of the electrode lead usingimage guidance can take place hours, days, or weeks following a repairprocedure. Placement of the electrode may also occur prior to a nerverepair procedure. Such placement may elicit an electrical stimulationconditioning effect of the cell body. Image guidance may be performedusing ultrasound, fluoroscopy, x-ray, or other imaging modalities.

In some embodiments, the markers comprise one or more protrusions and/orrecesses (e.g., dimples or reverse dimples). In such configurations, theprotrusions, recesses and/or similar features can serve a dual ormulti-faceted purpose or function. For example, not only could suchfeatures function as a fiducial marker, but they can also help restrict(or limit) movement of the lead when placed inside an object (e.g.,cannula, sheath, another cylindrical object, another object with one ormore openings, etc.).

In some embodiments, as illustrated, by way of example, in FIG. 17C, thelead housing 254 comprises a textured, ribbed and/or other non-smoothsurface 286. Such a configuration can help increase the contact surfacearea and improve localized anchoring of lead in situ with neighboringtissue. For instance, circular or linear substructures can be includedthat protrude from the surface (e.g., in a winged-like manner). Inaddition, or in lieu of such embodiments, recessed features may beincluded. For example, such recessed features can be depressed withinthe surface of the material. In some embodiments, substructures may beshaped or differently sized as to limit or enhance prevention ofmovement in certain directions, while facilitating movement in others asto provide improved temporary immobilization of lead in situ. In yetanother embodiment, substructures may include a single or multiplerings, hook-shaped structures and/or any other anchoring features ormembers 288 to improve or otherwise enhance anchoring of the electrodelead with suturing, or similar, to neighboring tissue. In otherarrangements, fibrin glue or similar tissue adhesives may be used totemporarily anchor the electrode lead. Such designs can be advantageousto users in order to affix stimulating leads in close proximity totargeted nerve tissue, ensure minimal or reduced unintended movement,facilitate removal of the lead with minimal disturbance to tissues oncestimulation is complete and/or provide one or more other advantages orbenefits. By way of an example, a user can place the lead parallel orapproximately parallel or tangential to a targeted nerve structure, andif desired, use standard medical sutures and/or other fixationtechnologies to engage flexible structures on the lead to anchor totissue.

In some embodiments, as illustrated in FIG. 17D, the percutaneouselectrode lead 250 comprises multiple conductive elements, 252, 258. Theconductive elements 252, 258 can include different shapes, sizes and/orother characteristics, as desired or required. For example, asillustrated in FIG. 17D, the conductive element at the tip 252 of theelectrode lead can be shaped in a manner to cap the electrode leadhousing 254 and also provide a larger surface area that may be used toprovide stimulus current to tissue such as peripheral nerves. Withcontinued reference to FIG. 17D, a second conductive element 258 can beshaped as a ring with said ring varying in thickness from 0.1-10 mm(e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8,0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 2-8, 3-6,1-3, 3-5, 5-8 mm, ranges between the foregoing, etc.) and can bephysically coupled to a conductive insulated wire 260. In somearrangements, a second conductive element 258 can be used as a returnelectrode for the first conductive element essentially creating abipolar stimulating field. In other arrangements, the second conductiveelement is used as a signal path for other circuitry and is combinedwith additional conductive elements placed on the lead. The plurality ofconductive elements can also form an electrical stimulation arrayallowing to shape or otherwise modify or impact the current field.

In some embodiments, as illustrated in FIG. 18A, the percutaneouselectrode lead 250 is coupled to a cap element that comprises anenclosure 262 (e.g., a shaped, plastic or other elastomeric orelectrically non-conductive enclosure or member) and a conductivesurface 264. In some arrangements, the conductive surface 264 is largerthan the enclosure 262. The plastic enclosure 262 can be greater thanone but less than twenty times the diameter of the electrode lead (e.g.,1 to 20 times, such as, 1-5, 2-4, 5-10, 10-20, 5-15, values between theforegoing, etc.), as desired or required. In some arrangements, thepercutaneous electrode lead 250 that comprises a conductive element atthe tip 252 (as previously described herein), may be in physical contact(e.g., at least partial physical contact) with the larger conductivesurface 264 present on the cap, effectively creating a largerstimulating surface. As an example, if the electrode lead is coupled toa pulse generator, covered with the described cap, and said pulsegenerator outputs a long duration pulse (e.g., a pulse having awavelength greater than 200 μs), the larger conductive surface of thecap may be used to stimulate muscle tissue. In the context of verifyingstimulus output, this may be advantageous since a smaller conductivesurface (e.g., as included on an electrode lead) may not create asufficiently large electric field to elicit a visual muscle contraction.The use of the larger conductive surface on the cap to stimulate musclecan arise, for instance, in situations where an intact uninjured motornerve is not readily accessible for stimulation. Using the cap to createa visual contraction in the muscle can provide enhanced confirmation tothe user that stimulus is being output to the electrode.

In some arrangements, the cap may be shaped similarly to a pen-likestructure to facilitate holding, grasping, manipulation, use and/or thelike. In such an arrangement, the cap may function as a nerve locator.In some embodiments, the cap may include a monopolar probe or a bipolarprobe. These probes can be configured to provide a smaller conductivesurface for fine resolution of the stimulating field in order to mapanatomical location of nerves. These arrangements can advantageouslyallow for a multi-function system providing both nerve locationfunctionality and neuroregenerative functionality.

In some embodiments, the cap comprises two or more pieces or portionsthat snap-fit together around the electrode lead. In other embodiments,any other type of connection or attachment method or technology can beused, such as friction or press fit, couplings (e.g., standard ornon-standard), mechanical fasteners or other mechanical connections,etc.

In some embodiments, the enclosure 262 (e.g., shaped enclosure) includesspace for embedded circuitry. In some arrangements, the enclosurecomprises a shaped plastic enclosure. FIG. 18B provides a cross-sectionview of the cap with reference to the plane 265 drawn in FIG. 18A andincludes the potential space for circuitry 266. In some embodiments,such circuitry comprises one or more assemblies 270, such as illustratedin FIG. 18C. In one example, as shown, the assembly 270 comprises twoconductive components, a distal component 272 and a proximal component280 that interface with a printed circuit board 274. The printed circuitboard can include passive and/or active components. In some embodiments,the printed circuit board 274 comprises a resistor 276 and a LED 278.

In yet other embodiments, the circuitry comprises a combination ofindicators and controls, including, by way of example, one or more LEDs(and/or other indicators) and/or one or more buttons or other controlsor controllers. Such a design can be advantageous to users in order toactivate pulse generation, verify functional output at tip (e.g., by wayof an illuminating LED) and/or in one or more other manners. By way ofan example, a user can connect the electrode lead 250 to a pulsegenerator, activate pulse generation using the button on the electrodecap and verify function by observing LED on the electrode cap. Such abutton, control or other controller can also be configured to change thestimulus amplitude and/or one or more other stimulus parameters (e.g.,frequency, pulse width and/or the like), as desired or required for aparticular application or use.

FIG. 18D illustrates the electrode cap 261 with the embedded assembly270 of FIG. 18C. In some embodiments, the distal conductive component272 is coupled (e.g., physically connected) to the conductive surface264 on the cap. When the cap is fully assembled relative to theelectrode lead 250, the proximal conductive component 280 of the cap canbe in physical contact with a conductive element 258 on the electrodelead, as depicted, for example, in FIG. 18E.

In some arrangements, when the cap is appropriately shaped and otherwiseconfigured, connection of the conductive tip 252 of the lead to thedistal conductive component 272, along with connection of the secondaryconductive element on the lead 258 to the proximal conductive component280, can allow for current to flow from the lead tip, through thecircuitry in the printer circuit board 274 and out to the secondaryconductive element 258 on the lead. Such a design can be advantageous topermit users to test if the conductive tip is functional.

By way of an example, a user can connect the electrode lead 250 to apulse generator. When a pulse is elicited from the generator, providedthe conductive tip 252 is not damaged and the cap is interfacedappropriately with both the conductive tip 252 and the secondaryconductive element on the lead 258, current may flow through the circuitboard and activate the LED or other indicator. Thus, visual confirmationcan be provided to the user that current is flowing through theconductive tip 252. In some embodiments, confirmation of current flow toconductive tip may be provided in one or more forms, including, withoutlimitation, visually, audibly, haptically and/or in any other manner,including combinations of the foregoing. Such a configuration can beincorporated into any of the implementations disclosed herein orvariations thereof.

According to some embodiments, the adhesive patch 80 includes an exposed(e.g., at least partially) conductive contact 282 as shown in FIG. 19.Additionally, the adhesive patch 80 can include one or more LEDs (and/orother visual indicators) 284 that can be coupled (e.g., directly orindirectly) to the conductive contact through one or more resistive orother elements. By way of an example, as shown in FIG. 19, the adhesivepatch 80 can comprise a percutaneous electrode lead 250 (e.g., inaccordance with those described herein or equivalents thereof). In somearrangements, for a user to test if the conductive tip of the lead 252is functional, practitioner or other user can place the tip 252 inphysical contact (e.g., at least partial physical contact) with theexposed conductive contact 282 on the adhesive patch. In someembodiments, provided that the patch is outputting a stimulus pulse, aparticular action by the user (e.g., depressing a switch 184), the LEDor other visual or other indicator 284 can be activated (e.g.,illuminated), thereby providing visual confirmation that the conductivetip is functional and is able to pass stimulus current. In someembodiments, confirmation that conductive element is functional mayinclude visual, audible or haptic indication, or a combination thereof.

In some embodiments, the patch 80 comprises a microcontroller and astimulus generator such that the stimulus generator outputs a lowamplitude AC waveform that in some embodiments may be used as averification signal. In some embodiments, by way of example, theamplitudes are 0.1 μA to 10 μA (e.g., 0.1-0.2, 0.2-0.3, 0.4-0.5,0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7,7-8, 8-9, 9-10, 0.1-1, 0.5-2, 1-5, 5-10 μA, values between theforegoing, etc.). In other embodiments, the amplitudes are less than 0.1μA (e.g., 0.01-0.1, 0.005-0.001 μA, less than 0.005 μA, etc.) or greaterthan 10 μA (e.g., 10-15, 15-20, more than 20 μA, etc.), as desired orrequired. AC waveforms may include a square wave, sinusoidal wave, orother alternating current waveforms at frequencies greater than 1 Hz(e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10 Hz, frequenciesbetween the foregoing ranges, greater than 10 Hz, etc.) or frequenciessmaller than 1 Hz (0.01-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-1,0.3-0.7 Hz, frequencies between the foregoing ranges, etc.).

In some embodiments, the stimulus generator is coupled (e.g., physically(e.g., directly or indirectly), operatively, etc.) to the electrodelead. In some embodiments, the microcontroller is programmed to preventoutput of stimulus pulses (such as, for example, the pulses that havebeen described herein) until the verification signal has been applied toan exposed conductive contact 282, as shown, for example, in FIG. 19.Such a “verify to unlock” feature can be advantageous to users as itverifies (e.g., directly) the functionality and integrity of theelectrode lead 250 and conductive tip 252.

In some embodiments, the electrode lead wire is coupled to cuffelectrode apparatus 10 (e.g., such as those apparatuses describedherein, variations thereof and/or any other type of cuff electrode). Toverify output of the cuff electrode, a verification bar 290, such as theone illustrated in FIG. 20A, can include one or more conductive elements292 and can be placed within a wrapped or unwrapped cuff electrode.

According to some arrangements, as illustrated in FIG. 20B, a cuffelectrode apparatus 10 with a monopolar electrode configuration (e.g.,such as any of the embodiments thereof described herein) is configuredto interface with the verification bar 290 or similar features orportion. In some configurations, a conductive element within theverification bar is in physical contact (e.g., at least in partialphysical contact) with the monopolar electrode within the cuff. Further,the conductive element can also be coupled to a conductive element thatis at or near the tip of the bar and in an area that is not wrapped bythe electrode. In some embodiments, a user can selectively verifystimulus output of the cuff electrode apparatus 10 by placing theexposed conductive tip on an exposed contact surface used for leadtesting such as the previously described exposed contact on a patch usedfor lead testing 282. This process of verification is similar to thosedescribed herein when using a percutaneous lead wire with conductive tipand can be applied to any embodiments disclosed herein.

In certain embodiments, the verification bar 290 includes one or moreLEDs and/or other visual indicators for testing verification 284. In oneexample, as illustrated in FIG. 20C, the verification bar 290 comprisesa conductive element 292 that is in contact with an electrode of anelectrode apparatus 10 (e.g., such as those described previouslyherein). The conductive element 292 of the verification bar 290 can becoupled to a LED or other visual indicator, which is coupled (e.g.,operatively, electrically, etc.) to a second conductive element 292. Auser can verify stimulus output of a cuff electrode apparatus 10 byplacing the exposed conductive tip on an exposed contact surface usedfor lead testing (e.g., the previously described exposed contact on apatch used for lead testing 282). In some embodiments, activation of theLED or other indicator 284 within the verification bar can indicateproper current conduction from the electrode apparatus 10.

In some embodiments, the verification bar 290 is designed and otherwiseconfigured to interface with a multi-contact electrode apparatus. In oneexample, as shown in FIG. 20D, the verification bar 290 comprises twoconductive elements 292 such that each conductive element 290 of theverification bar is in physical contact (e.g., at least in partialphysical contact) with a separate electrode of a cuff electrodeapparatus 10. In some embodiments, the verification bar 290 thatinterfaces with multiple electrodes can include one or more LEDs and/orother visual or other indicators, as desired or required. With continuedreference to the example depicted in FIG. 20D, verification of thestimulus output can be advantageously performed directly at the level ofthe electrode apparatus without use of a separate exposed contactsurface for lead testing. In some embodiments, the verification bar 290may be physically coupled to the adhesive patch 80.

In some embodiments, the percutaneous electrode lead 250 with multipleconductive elements 258 (e.g., as described herein), is coupled (e.g.,physically, electrically, operatively, etc.) to a stimulation sourcethat can include circuitry to test the connectivity and placement of theelectrode lead. In some arrangements, the stimulation source can also beconfigured to provide neuroregenerative therapy (e.g., via the deliveryof stimulation energy). One such embodiment, which can be termed afunctionalized electrode, is illustrated in FIGS. 21A and 21B. In someembodiments, such an electrode can comprise a percutaneous lead coupledto a housing that may include a stimulation source.

In some embodiments, as illustrated in FIG. 21C, verification of thestimulus output can be performed by inserting one or more conductiveelements of the lead into a housing 114 of an electrical stimulationapparatus that comprises of verification test elements, as describedherein. In some embodiments, such a stimulation apparatus can includeone or more visual elements 284 and/or can include another type ofindication to the user (e.g., audible indication, haptic indication,etc.) to notify a user that the stimulus output is verified.

According to some embodiments, the housing of the electrical stimulationapparatus comprises a pull-tab 187 (e.g., as described herein withreference to other embodiments). In some arrangements, a stimulationapparatus includes one or more verification mechanisms or features tohelp place the system in an “unlock” mode (e.g., as also describedherein). By way of example, a percutaneous electrode lead with multipleconductive elements can be packaged with one or more conductive elementsinserted into the housing of a stimulation apparatus with a pull-tab orsimilar feature. When a user removes the pull-tab, the stimulationapparatus can notify (e.g., immediately notify, such as within less thanone second) a user the status of the stimulus output using the indicatorthat is included in the corresponding device (e.g., visual indicator,audio indicator, haptic indicator, combination thereof, etc.). In otherembodiments, notification to a user can take other forms (e.g., othertypes of indication, within other time frames, etc.), as desired orrequired. The status may be used to “unlock” or turn on stimulationcircuitry or prevent the circuitry from being powered. This may beadvantageous to a user in that the appropriate functionality of thepulse generator and the electrode lead integrity may be evaluated in asingle step and without the need of placing the lead on or nearexcitable tissue and delivering stimulus pulses.

In some embodiments, the pull-tab may be replaced by a tactile switch185 or other type of switch. In some arrangements, the stimulationapparatus includes multiple indicators (e.g., visual, audible, haptic,other indicators, etc.) that may be used to provide (e.g., display)information, including, without limitation, time, relative stimulusamplitude 118 and/or the like.

According to some arrangements, shown in FIGS. 22 and 23, the device orsystem is used to first locate a nerve 300, 310, and if an injured nerveis found or otherwise detected 302, 312, to provide neuroregenerativetherapy to it 304, 314. In some embodiments, the device or system isused only as a nerve locator or only as a regenerative therapy system.However, in some configurations, it is advantageous for the device orsystem to be adapted to do both the detection and subsequent delivery ofenergy (e.g., for neuroregenerative therapy). Such features can beincorporated into any of the device or system embodiments disclosedherein.

In some embodiments, the device or system comprises a single controlbutton or other control or controller (e.g., which can take the form ofsomething other than a button) used to switch between a first phase ofstimulation and a second phase of stimulation. Such a button or othercontrol or controller can also be used to adjust stimulus outputparameters and control visual indicators and/or conduct any otherfunction, as desired or required.

Intraoperative Nerve Location and Therapy

According to some arrangements, one intended use of the system is in theoperating room. Thus, the system can be designed, customized andotherwise configured with such intended use mind. The various systemsdisclosed herein can advantageously function and operate as adual-purpose device serving the needs of both nerve locationfunctionality and nerve (e.g., neuroregenerative) therapy.

In some embodiments, the housing of the system comprises a bipolar probetype electrode used for nerve location purposes with a port used toconnect a cuff-type electrode that can be used to interface with aninjured nerve to deliver neuroregenerative therapy to injured nervetissue. The bipolar electrode apparatus may be similar to any of theones described in greater detail herein. In one embodiment, the injuredtissue is a peripheral nerve. However, in other arrangements, theinjured tissue can include any other type of nerves, such as autonomicnerves. In other embodiments, a bipolar electrode may be one of varioustypes that are common to those skilled in the art. In suchconfigurations and uses, the surgeon or other practitioner canphysically connect an electrode with lead wire and connector to a jackor other coupling location located on the housing unit. A flow diagramof one embodiment of usage of a dual-purpose device is schematicallyillustrated in FIG. 24 and described in greater detail below.

In one embodiment, as illustrated in the example of FIG. 24, when thesystem is first powered on 354, it is configured to enter a “test” mode.In one example, the test mode is adapted to assist in locating nerves356. The test mode can comprise pulse trains, with each stimulus pulsecomprising a doublet pulse (e.g., separated by a particular inter-pulseinterval). For example, in some embodiments, the inter-pulse intervalcan be 5 ms, as described herein and shown in, for example, FIG. 6A.However, in other arrangements, the inter-pulse interval can be lessthan or greater than 5 ms, as desired or required (e.g., 0-5 ms, 5-10ms, greater than 10 ms, etc.). The pulse trains can be applied to atargeted nerve to test the integrity and function of the connectedmuscle 358. The doublet pulses can be configured to increase (e.g.,maximize) or otherwise enhance the torque time interval and reducestimulus amplitude requirements.

In some embodiments, the pulses are output at a frequency of 10 Hz orlower to provide a tetanic like contraction. The frequency range mayinclude 0.1-40 Hz (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-1, 1-2,2-3, 3-4, 4-5, 5-10, 10-15, 15-20, 20-30, 30-40 Hz, frequencies withinthe foregoing ranges, etc.).

In some embodiments, the amplitude of the stimulus can be configured tobe adjusted 360 until a desired response is reached 362. If the user issatisfied with the testing of a targeted nerve, he/she can selectivelychoose to test other nerves 364, and the process of adjusting amplitudescan be repeated. In some embodiments, once the desired response for anerve that was to be tested is reached, the user can be done using thesystem 366.

In some embodiments, with continued reference to FIG. 24, when a user issatisfied with locating nerves and/or when a determination is made thata nerve is injured 368 (e.g., the nerve is injured given a particularthreshold level or response), the practitioner can connect an electrode(e.g., a cuff-type electrode, any other type of electrode, etc.) to anerve port located on the housing 370. Any other type of electrode canbe used, as desired or required. The system can be configured to detectthe electrode 372 and appropriately direct the stimulus output from theprobe to the electrode. When this occurs, the system mode can beswitched to neuroregenerative treatment mode 374. The stimulus amplitudecan be changed 376 until a desired response is reached 378. The user canthen initiate treatment 380 of an injured nerve using neuroregenerativetherapy. In some embodiments, the system comprises a timer that limitsthe duration of neuroregenerative therapy 382 and checks to ensure thatthe total time was not exceeded 384. In such embodiments, once theprescribed or required time requirement has been reached, the system canbe configured to shut off 386 (e.g., automatically, according to apredetermined protocol or algorithm). Further, the system can beconfigured to provide the practitioner with an appropriate indication orcue (e.g., a visual cue, audio cue and/or any other indication).

In some embodiments, intraoperative use of the system can comprisehands-free usage (full or partial hands-free usage). For example, thesystem can operate in a mode so that it may be placed within theoperative field and require minimal or reduced attention from operativestaff during the period of stimulation. As previously discussed, theshape of the housing can be used to prevent the system from rolling offthe operative table or sterile towels that are placed on a patient.Additionally, as also discussed herein, the inclusion of aspecially-shaped (e.g., hook-shaped) extension element or other featurecan assist the user to couple the system to an IV pole or otherstructure in relative proximity to the subject being treated.Advantageously, these features can permit and facilitate hands-free usewith minimal or reduced intervention from operative staff. In somearrangements, the system is single use, and hence, once turned on orotherwise activated, the system can no longer be turned off. Forexample, in some arrangements, when the pull-tab is removed, engagingpower the source, the device has a finite functional period dictated bythe battery life. In some embodiments, the pull-tab may be replaced byan on/off switch or similar feature or component, thereby making thedevice reusable.

Peri-Operative Use

As noted herein and described in greater detail below, any systemembodiments disclosed herein can be also be used in a peri-operativesetting or application. For example, in some embodiments, a system inaccordance with the various arrangements described herein can beconfigured to connect to a mono-polar electrode (e.g., serving as theactive stimulating electrode or cathode). Such a monopolar electrode cancomprise various forms including and without limitation, a needleelectrode, a catheter or cylindrical type electrode and/or the like thatmay be placed close to an injured nerve percutaneously or be placedclose to the nerve when the injured nerve is exposed. As disclosedherein, any other type of electrode can be incorporated into a device orsystem design or the execution of a treatment method.

In some embodiments, a monopolar lead is substituted as the nerve probeand a return electrode is connected to the nerve port. In someembodiments, a multi-conductor electrode lead is connected to the nerveport. One of the conductors of the system can connect to a monopolarlead placed within the patient while a second conductor may be connectedto a return electrode such as a surface pad or needle. In someembodiments, the nerve probe is not present requiring only connection tothe nerve port in order to output electrical stimulation pulses, asshown, for example, in FIG. 21A. Some embodiments of the system can beadvantageous in certain indications and for certain uses, such as, forexample, carpal tunnel release surgery.

In both use cases outlined above (e.g., both in the intraoperative andperi-operative contexts), the system is not necessarily limited to beused in the manner described for those use cases. For example, theperi-operative use case may also be applied intraoperatively if theend-user decides it more appropriate to stimulate using a monopolarelectrode lead or similar lead.

FIG. 25 outlines a flow diagram of one embodiment of usage of aperi-operative system (e.g., such as a patch described herein). In oneembodiment, a user places an adhesive patch 80 on the skin of a patient402. The location of the patch is not specific, and in some embodiments,it is satisfactory as long as it is in at least partial physical contactwith the skin of the patient or subject. In one embodiment, the built-instimulus generator within the patch is activated by pressing a switch orother controller 404. The switch or other controller can be identical orsimilar to those described herein.

According to some embodiments, the output of the pulse generatorcomprises single pulses, pulse trains, doublet pulse trains or any othertype of pulses. The pulses can be constant voltage or constant currentpulses with amplitudes sufficient to depolarize a nerve or muscleprovided the appropriate electrode contact and/or other operationalparameters are used. In one arrangement, once the stimulus generator isactivated, the user may want to verify the stimulus output 406. In someembodiments, such verification is accomplished in one or more steps, inaccordance with one or more of the configurations described herein.

In some arrangements, the user may observe the stimulus output LED 82 onthe patch itself 408 (and/or be alerted of stimulus output using anothertype of visual, audible, haptic and/or other indicator or output). If anelectrode cap, similar to the embodiments described herein, is assembledwith the electrode lead, the user can observe a LED (or other indicator)within the cap turn on when the stimulus is output 410.

According to some arrangements, where no cap is present, the user cantouch the electrode lead to a conductive surface used for testing outputon the patch itself 412, when connected a LED on the patch will turn on.In some arrangements, where no cap is present, and a cuff electrodeapparatus 10 is used, the user may verify the stimulus output bytouching the exposed contact on the verification bar within the cuff (ifpresent) to a conductive surface used for testing output on the patchitself. In some arrangements, the cuff apparatus 10 may comprisemultiple electrodes in a bipolar or multi-polar configuration.Verification of the stimulus output in this arrangement can includeobserving if the LED or other indicator of the verification bar isactivated (e.g., turns on).

In some embodiments, if any or all of the described verification stepsabove are negative, the user can stop 414 the procedure and remove thepatch as the stimulus generator or electrode lead may be defective. If,however, one or more of the tests are positive, the user can continuewith the procedure. In one embodiment, for instance, during a surgicalprocedure with an open incision, the user can additionally verify theoutput by either using the larger conductive surface of a cap 416 or theconductive lead tip on to touch exposed intact and uninjured nerves ornearby muscles.

In some configurations, if the user is satisfied with the output and thecap is connected, the user can remove the cap 418 and place the leadadjacent (e.g., next to) an injured nerve that is to be treated withneuroregenerative therapy 420. In some embodiments, the user cancomplete the surgical procedure 422 and suture the wound closed whilemaintaining the exposed percutaneous lead 424 is exiting the woundappropriately.

According to some arrangements, a patient may then be removed from theoperating room and a user, such as a nurse, can connect a secondstimulation unit to the patch connector 426. The second stimulation unitcan be turned on and initiates neuroregenerative therapy of the injurednerve 428. The user may adjust stimulus amplitudes throughout the courseof the therapeutic time 430. If a desired response is achieved 432, andthis may be based on patient feedback, muscle contractile response orother metrics, the user can, in some embodiments, leave the stimulationunit to complete the therapy. When the therapy has been completed 434,the stimulation unit is turned off 436, and the electrode lead isremoved from the body 438 and the procedure can be completed 440.

In some embodiments, a first stimulation unit can provide bothverification stimulus pulses used to test nerves, muscles, and/or verifyfunctionality of the electrode and/or system and also contain necessaryhardware to provide neuroregenerative therapy without requirement of asecond stimulation unit.

A flow chart of the functionality of such a system is provided in FIG.26. As illustrated in the example embodiment of FIG. 26, when power isapplied to the system, e.g., via removal of a pull-tab 322, the systemcan be configured to operate in a self-verification state 324.Self-verification can include touching an electrode to an exposedcontact on the system housing or placing the lead within the systemhousing, as described herein. In some embodiments, self-verificationcomprises placing the electrode on an exposed or recessed contact with astimulation source providing a characteristic frequency pattern used to“unlock” the system. In some arrangements, when the system has completedself-verification 326, it can be used to locate (e.g., “test”) nerves330. In some arrangements, an accessory or component of the device orsystem, e.g., such as a cap or hand-held attachment, may be clipped orotherwise attached (e.g., directly or indirectly) to the electrode leadto facilitate grasping and usage as a hand-held nerve locator.

With continued reference to FIG. 26, an injured nerve is located 332,either using the system itself or is determined apriori by a user (e.g.,practitioner, medical professional, through some other mechanism orprotocol, etc.), the electrode lead may be temporarily implanted 334using an insertion tool (e.g., in accordance with embodiments disclosedherein). The method of implantation can rely, at least in part, on usingtissue (e.g., preferably non-dissect or non-undermined tissue) in thepara-incision area to support the anchoring of the lead and reduce orminimize lead movement in the lateral direction (e.g., perpendicular tothe longitudinal axis of the lead). Once implanted, the stimulationamplitude and/or stimulation energy delivered can be adjusted, and asecondary verification 336 can take place to ensure adequate electrodeplacement. This verification step may comprise of measuring current flowbetween anode and cathode electrodes, measuring action potentials in anerve, measuring motor or sensory responses and/or any otherverification step or method, as desired or required. The stimulusparameters used for this secondary verification step may comprise arepetitive burst sequence with at least two pulses. In some embodiments,the repetitive burst sequence comprises at least three pulses (e.g., 3,4, 5, more than 5, etc.). When a desired response to the verificationhas occurred 340, neuroregenerative therapy may commence on the injurednerve 342. The system can be configured to provide neuroregenerativetreatment to injured nerves for the appropriate amount of time, asdisclosed herein. When such time has elapsed 344, the electrode may beremoved from the body 346, and both the electrode and stimulation sourcemay be disposed of 348.

In some embodiments, the insertion tool may comprise an over-the-needlecatheter assembly. Such assemblies may be utilized to deploy anelectrode in a series of steps as outlined and shown, by way of example,in FIG. 27. According to some embodiments, in order to minimize orotherwise reduce the impact of a surgeon's workflow, an insertion toolis used to place an electrode in the para-incisional area as previouslymentioned (FIGS. 27A-27C). In some arrangements, this is advantageousfor one or more reasons. For example, such a configuration can prevent alead wire from protruding (e.g., partially or completely) through anexisting incision site. Such protrusions are generally moretime-consuming to suture around, and in cases of removal, may damageunderlying structures such as a repaired peripheral nerve and the like.

According to some embodiments, once a viable para-incisional pathway hasbeen created using an insertion tool, an electrode lead may be advanced(e.g., fed through using such a pathway) towards an injured nerve (see,e.g., FIG. 27D). In some embodiments, a trocar (e.g., a trocar, anothertype of hollow tube with or without a sharp end, etc.) may be used tocreate an access point. Such a trocar is typically used by creating anaccess point starting from the inside of the body and pushing throughtissue towards the skin. In some embodiments, once the trocar has exitedthe skin, an electrode may be fed through the trocar to the target site.In other embodiments, a robotic surgery unit may be used topercutaneously place an insertion tool or a trocar. In somearrangements, for therapeutic efficacy, it is important to maintain anelectric field that is proximal to the nerve injury/repair site.

Electrical stimulation across a nerve gap can be used to slowly increaseneurite growth across the gap. These signals can be low level (e.g.,sub-threshold) DC currents. In contrast, in some arrangements, ACstimulation that results in an electrical field sufficient to createaction potentials on the proximal aspect of an injured nerve thatconduct towards the neuron cell body upregulate regeneration associatedgenes leading to accelerated axonal regeneration.

According to current protocols and treatment techniques, severalmethodologies can be used to deliver AC stimulation to accelerate nerveregeneration. Such methods include placing two (e.g., separate) wires(e.g., fine-gauge stainless steel wires) on the proximal aspect of theinjured and repaired peripheral nerve. Typically, the anode is placed onthe most distal aspect of the injured proximal nerve stump, while thecathode is placed further proximally. Such an arrangement ofanode/cathode can be used to avoid or reduce the likelihood of potentialto induce an anodal block. However, in such embodiments, wires areplaced within the surgical incision, requiring a surgeon to carefullysuture around these wires when closing the main procedural incision.

In another clinical study, a monopolar cuff electrode is used to deliverAC stimulation to accelerate nerve regeneration. However, in suchconfigurations, the usage of a cuff electrode mandates that thestimulation procedure takes place intraoperatively as percutaneousremoval of a cuff electrode is not possible without incurring nerveinjury.

In a third clinical example, AC stimulation used to accelerate nerveregeneration employs the usage of a monopolar fine needle electrode.While needle electrodes may be placed in the para-incisional area, thesharp tip used to create a pathway through tissue may also inadvertentlypuncture the injured nerve that is to be stimulated. Additionally, therigid nature of needle electrodes allows them to easily be dislodged ormoved. In some situations, this creates challenges for the clinicianemploying AC stimulation for accelerated nerve regeneration in thatmovement of the active electrode may reduce or eliminate therapeuticeffect (e.g., any or a required amount of therapeutic effect) due to amore distant electric field that may not be sufficient to depolarizeinjured axons.

The methods and systems described in this disclosure help avoid or atleast reduce the likelihood of the negative issues described in thecurrent clinical utilization of AC stimulation for accelerating nerveregeneration.

With continued reference to FIG. 27D, a verification or validation stepmay take place in association with (e.g., during) the placement of theelectrode lead. In some embodiments, such a verification or validationstep comprises measuring current flow between anode and cathodeelectrodes, measuring action potentials in a nerve, measuring motor orsensory responses and/or any other verification step or method, asdesired or required. In some configurations, once the electrode ispositioned and one or more validation steps are completed, a secondphase of stimulation may be administered that can include therapeuticstimulation to enhance or otherwise improve nerve regeneration andtissue reinnervation.

Although, in some embodiments, the validation and therapeutic procedurecomprises two steps, such steps do not need to be completed as twoseparate events. In some arrangements, validation and therapy takesplace in two separate events. For example, a validation step (e.g., afirst stimulation phase) can occur during the event of locating a nerveor measuring a patient response (e.g., sensory, motor, verbal, etc.),while a therapeutic step (e.g., a second stimulation phase to provideneuroregenerative therapy) follows. In some embodiments, these twoseparate events occur one after another (e.g., in series). In otherwords, the event of locating a nerve and the event of providing therapyare separate events, but such separate steps still employ a two-phasestimulation approach.

With continued reference to the embodiments where validation andtherapeutic stimulation occur as separate steps in series (e.g., oneafter another), the subsequent therapeutic step can be configured tooccur immediately after the validation step ends. In otherconfigurations, a delay exists between the termination of the validationstep and the subsequent therapeutic step. In such embodiments, the timedelay between the two steps is 0 to 5 seconds (e.g., 0-0.05, 0-0.1,0.1-0.5, 0-1, 1-2, 2-3, 3-4, 4-5, 0-2 seconds, time ranges between theforegoing values, etc.).

However, in other embodiments, the same devices and systems describedherein are adapted to complete the two-step validation and therapeuticprocedure in one physical event (e.g., not as separate events). By wayof specific example, the stimulation system can be implanted andactivated (e.g., turned on) to deliver neuroregenerative therapy. Insome embodiments, if a therapeutic stimulus pulse is delivered every 50ms, for example, sufficient time between consecutive pulses can beprovided to deliver validation stimuli as further described below. Theresponses to the validation stimuli can be used as a decision point toproceed or continue with delivering neuroregenerative therapy. In someembodiments, such a single event (e.g., implant stimulator andactivation) still employs two phases of stimulation albeit occurringduring one single event.

In some embodiments, the therapeutic pulse itself may satisfy avalidation condition if it is of sufficient energy to evoke a biologicalresponse (e.g. an action potential).

FIGS. 27A to 27D provide only one example of utilization of thedescribed technology; however, the technologies described herein can beapplied to any injured nerve in the body. For example, as shown in FIGS.28A and 28B, the devices, systems and methods can be applied insituations where a median nerve was at least partially lacerated (and/orotherwise damaged) and repaired, and a stimulation electrode placedpercutaneously connected to a system is used to deliverneuroregenerative therapy. Another example is depicted in FIGS. 28C and28D, where a peroneal nerve was at least partially lacerated (and/orotherwise damaged) and repaired, and a stimulation electrode placedpercutaneously connected to a system is used to deliverneuroregenerative therapy. According to some embodiments, theconfigurations described above and in other places of the presentapplication are advantageously designed to be anatomy agnostic, that is,amenable to treat any injured nerve anywhere in the body. By way ofexample, nerves that can targeted for treatment using the devices,systems and methods described herein include, but are not limited to,nerves in the peripheral nervous system (e.g., median, ulnar, radial,peroneal, tibial, sciatic, etc.), the autonomic nervous system (e.g.,splanchic, phrenic, vagus, mesenteric, etc.), nerves arising ororiginating in the brain (e.g., cranial nerves such as facial,trigeminal, spinal accessory, etc.).

In some embodiments, an insertion tool comprises one or moreelectrically active components that are used to confirm a validationcondition. For example, a needle in an over-the-needle catheter assemblymay be physically connected to a stimulus source and be used to confirma validation condition. In other embodiments, the catheter may includeone or more (e.g. 2, 3, 4, 5, etc.) conductive elements that arephysically connected to a stimulus source used to confirm a validationcondition.

In some embodiments, the conductive elements on the catheter may be usedto detect a biological signal, such as, for example, an action potentialin an injured nerve. Such action potentials may be in the form ofindividual action potentials (spikes), compound motor action potentials,compound sensory action potentials, or a mix of these.

In some embodiments, the percutaneous electrode lead 250 with multipleconductive elements 258 (e.g., as described herein) may beadvantageously used to measure action potentials (FIGS. 29A to 29D). Inone example, a multi-element electrode lead is placed near an injurednerve. In some arrangements, the electrode can be positioned parallel orgenerally parallel to the longitudinal axis of the nerve. Proximalconductive elements 30 can be configured to measure an evoked responsein the injured nerve in response to stimulus derived from distalconductive elements. In some arrangements, such an “upstream”measurement is used (either alone or together with some othermeasurement or metric) to confirm a validation condition. In somearrangements, the recording electrode configuration comprises amonopolar, bipolar, tripolar, or other configuration, as desired orrequired by a particular design or application. In some embodiments, thedistal conductive tip 252 is configured to create a monopolar electricfield in conjunction with a distal reference electrode. In somearrangements, the distal reference electrode is a surface patchelectrode 80 (or some other type of surface electrode) with integratedelectronics. In yet another embodiment, the distal conductive tip 252with other conductive elements 258 is configured to create a bipolarelectric field. In some embodiments, more than 2 conductive elements(e.g. 3, 4, 5, etc.) are used to steer or otherwise direct current moreprecisely to target an injured nerve, specific fascicles within aninjured nerve and/or another targeted anatomical structure.

In some arrangements, a switching mechanism is used to switch electrodesfrom stimulation to recording. Such a configuration can be applied toany of the electrode embodiments disclosed herein. For example, a distalmonopolar stimulation electrode 252 may be used in a first phase ofstimulation to deliver a stimulus pulse in conjunction with a distalreference or return electrode, such as a patch 80 with integratedelectronics. In some arrangements, once the stimulus pulse has beendelivered, the distal stimulation electrode 252 may be switched to beconnected to a recording amplifier, and in conjunction with one or moreproximal electrodes 30 and a distal reference electrode, such as a patch80 with integrated electronics, may be used to measure biologicalsignals such as action potentials. A combination of these configurationsmay also be employed and not limited to what has been described herein.

In some embodiments, the stimulation system includes recording andamplification circuitry to measure biological signals. In someembodiments, amplification circuitry comprises instrumentationamplifiers, filtering circuits, or other analog amplificationcomponents. Such amplification circuitry can also be configured tointerface with an analog-to-digital converter that converts measuredanalog signals to a digital format. In some arrangements, such digitalsignals are further manipulated in order to extract characteristicfeatures. Such features can include, but are not limited to, signalamplitude, area, power, frequency, phase, etc. In some embodiments, suchfeature extraction occur on a microcontroller or a similar controller ordevice.

In some embodiments, as depicted in FIG. 29E, a cuff electrode assembly10 may be used to monitor a validation condition. Such a cuff electrodeassembly may be connected to a single system that incorporates deliveryof stimulation and measurement of action potentials. In someembodiments, such a system can be configured to deliverneuroregenerative therapy.

For any of the embodiments disclosed herein, a measurement system orassembly may be a separate system from a stimulation system or assembly.In some arrangements, a separate measurement system can be configured tocommunicate wirelessly with a stimulation system (e.g., to confirm avalidation condition during a first stimulation phase, to provideinformation regarding the recorded signal characteristics, or to gate(e.g., provide a go/no-go signal) a second phase of stimulation whichmay comprise stimulation to enhance nerve regeneration or tissuereinnervation and/or the like). Wireless communication means caninclude, but are not limited to, radiofrequency protocols (e.g.,Bluetooth, Zigbee, Wi-Fi, NFC, etc.), optical communication (e.g.,infrared, near infrared, visible light), or magnetic (inductive links).In other arrangements, a wired connection (e.g., via cable) can be usedto permit communication between the different systems or assemblies. Insome arrangements, the separate system may be used to measure muscleaction potentials, nerve action potentials and/or other evokedbiological signals, as desired or required. Such potential and othersignals can be advantageous or otherwise beneficial in different injuryscenarios. For example, in the case of a compressive nerve injury (suchas, for instance, carpal tunnel syndrome), a connected muscle actionpotential measurement system may be used to measure an evoked muscleresponse from the partially denervated muscle and confirm a validationcondition. In another example, a separate system may be employed tomeasure action potentials from a nerve at a different anatomicallocation. Such nerve may be physically connected to the injured nerve(e.g., further upstream of the injury site), but not be openlyaccessible. Under such scenarios, a separate system can be used toconfirm a validation condition that may not be possible to confirm usingother described means. In some embodiments, the separate system usessurface or percutaneous electrodes to obtain a measurement.

In some arrangements, a stimulation system waits for an externalcharacteristic signature to validate operation (e.g., a validationcondition). In some embodiments, such a signature comprises discretestimulus pulses delivered by a separate stimulation unit. Measuredresponses to a signature may be used to confirm a validation condition.Such signatures may be elicited not only using electrical stimulationbut also using vibratory stimuli, acoustic, or light, or a combination.

In some embodiments, the separate measurement system is adapted andconfigured to measure, record and/or otherwise consider somatosensoryevoked potentials or other electrical activity of the brain that resultsfrom the stimulation of touch. By way of example, evoked potentials maybe elicited by stimulating an injured nerve on the proximal stump orconnected branches. This may elicit a response both in the spinal cordand in the brain that may be recorded using a separate measurementsystem. In some arrangements, such a separate measurement system is usedto confirm a validation condition. In any scenario, such recordings mayutilize surface electrodes that reside on the surface of the skin, or onthe dura (epidural electrode), or directly (subdural) on the spinal cordor brain.

In some arrangements, a surface patch 80 electrode with integratedelectronics is used as a reference electrode for a measurement of abiological signal (e.g., action potential) recorded by proximalconductive elements in the electrode lead. Such a surface patch 80 mayinclude one or more visual indicators 82. In some arrangements, suchindicators 82 can be used to advantageously provide data and otherinformation to a user, such as, for example, time, status, stimulusamplitude and/or the like.

In some embodiments, a measurement system is configured to send datawirelessly to a separate device or component, such as, for example, asmart phone, a tablet, another smart portable device, a separatecomputing device (e.g., a laptop) and/or the like. The separate deviceor component can include (or can be configured to use) one or morealgorithms to analyze data, confirm a validation condition and/orperform any other function. In some arrangements, such a smart or othercomputing device or component can be configured to communicate with oneor more stimulation devices to enable and/or facilitate the execution ofneuroregenerative therapy.

Regardless of the configuration utilized, in some embodiments, it isadvantageous, while measuring biological signals (e.g., actionpotentials), to maintain and/or otherwise consider or take into accounta running average of measured characteristics (e.g., amplitude, signalarea, signal power, frequency spectrum, phase, etc.) to enhance thesignal-to-noise ratio or another metric. In some arrangements, such anaverage comprises at least 2 instances of evoked responses.

In some embodiments, the measurements of biological signals during avalidation or verification step may be used to gate (e.g., provide ago/no-go signal) a second or other subsequent phase of stimulation,which may comprise stimulation to enhance nerve regeneration or tissuereinnervation.

To further elaborate on or otherwise supplement or enhance motor/sensoryresponses during a validation or verification step, in some embodiments,the repetitive burst sequence discussed herein creates a validationsignature or other unique identifier. Such a signature may comprisestimulus pulses with various characteristics (e.g., different pulsedurations, amplitudes, frequencies, etc.). In some arrangements, thevalidation signature is configured to synchronize with a display (orother output) and be used for direct patient and/or practitionerfeedback (e.g., asking patients if the response they feel fromstimulation is similar or dissimilar from what is shown on the display,querying the physician to assess a patient's response, etc.). In someembodiments, it is advantageous to use discrete pulses that may berandomly delivered during this validation phase. Such a configurationcan be advantageous because a constant frequency output (e.g., 20 Hzwith a fixed pulse width) may provide a “buzzing,” other constantsensation and/or another type of sensation to a patient. For example, inthe case of a severe nerve injury (e.g., a transection), such a constantsensation from stimulation may be masked or not interpreted asstimulation due to the injured axons randomly firing or beinghypersensitive. In some configurations, discrete pulses overcome thislimitation and may provide for objective measurement of a validationcondition (e.g., a patient response to stimulation). Additionally, itmay be advantageous to provide discrete pulses at a frequency below themuscle fusion frequency to prevent any fused muscle contractions. Insome embodiments, muscle fusion frequencies vary depending on themuscle. For example, such fusion frequencies may be greater than 100 Hzfor fast twitch ocular muscles or between 5 and 20 Hz (5-6, 6-7, 7-8,8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 5-10, 10-15, 15-20, 10-20Hz, frequencies between the foregoing ranges, etc.) for slow twitchmuscles such as the soleus muscle. In some arrangement, suchcontractions may arise if a transected nerve is stimulated proximal tothe injury and proximal to any non-injured nerve branches. Thesecontractions may also arise in nerves injured by compression where somedistal conduction is able to take place if said injured nerve isstimulated proximally. Non-tetanic pulse trains are able to beinterpreted as discrete events by a patient which may satisfy avalidation condition, in some embodiments.

In some embodiments, a validation signature or other unique identifieris used throughout a therapeutic stimulating window (e.g., during 1 hourof neuroregenerative therapy, some other duration of therapy, etc.).This validation signature may advantageously confirm to a user that thesystem is providing therapeutic efficacy to injured nerves undergoingstimulation. In some arrangements, the validation signature appliedthroughout the stimulating window may comprise one or more discretepulses (e.g. 2, 3, 4, 5 pulses, etc.) producing one or more (e.g. 2, 3,4, 5, etc.) evoked potentials. The timing between subsequent pulses(e.g., pulse frequency) may be uniform or non-uniform (e.g., random), asdesired or required. In some arrangements, such evoked potentials can beaveraged to create a composite validation response that may confirm to auser if stimulation is applied correctly and the system is providingtherapeutic efficacy to injured nerves.

Multiple Nerve Injuries

In cases such as brachial plexus injuries, where multiple nerves areinjured, it may be desirable to provide neuroregenerative therapy to allinjured nerves at once. In such instances and arrangements, the systemcan be designed and configured to output to different electrodeconfigurations. See, for example, FIG. 30.

In some embodiments, as illustrated in the example of FIG. 30, anelectrode apparatus connector 208 with an analog demultiplexer 210controlled by the system can be connected to the nerve port. In somearrangements, this permits the system to provide output to one channelat a time by switching between channels 212.

In some embodiments, the nerve port comprises additional conductivesignal paths or lines for carrying power and control information to theanalog demultiplexer. In some embodiments, the connector may featureconnections to control an analog demultiplexer using either a parallelconfiguration where one control signal line is needed for each electrodeconnected to the system (e. g. ON Semi MC14067B, Analog Devices ADG5412,Maxim Integrated MAX4623, or equivalent). In other arrangements, theconnector can include three control signals for interfacing to an analogdemultiplexer using the serial peripheral interface (SPI) (e.g. AnalogDevices ADGS1412).

According to some embodiments, a cable containing the multipleelectrodes can comprise a connector housing unit that include thedemultiplexer circuit and indicators, such as, for example, LEDsdisplaying the active channel. In yet other arrangements, the connectorhousing unit can include memory and an energy source (e.g., a relativelysmall energy source, such as, for example, such as a coin cell batteryor the like) to power said memory. In some arrangements, the memory isconfigured to store information, for example, stimulus settings, otheroperational parameter and/or the like. In some arrangements, theconnector housing unit can include memory, energy source, demultiplexercircuitry and/or any other features or components, as desired orrequired. Each lead wire connected to an electrode apparatus can includea connector housing unit that comprises one or more of the componentsdescribed in greater detail with reference to any of the embodimentsdisclosed herein.

Treatment Method Duration

In terms of therapeutic time duration, studies have demonstrated theoptimal duration to be as little as 10 minutes or 30 minutes. However,most studies utilize a treatment duration of or near 1 hour. Theduration of a treatment method can therefore be between 10 and 90minutes (e.g., 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90,10-30, 30-60, 40-80 minutes, times within the foregoing ranges, etc.),as desired or required. In other embodiments, a treatment procedure cantake longer than 90 minutes or less than 10 minutes.

In some embodiments, the treatment of injured nerves comprises theset-up of an appropriate electrode apparatus and stimulus parameters,the initiation of treatment, and the maintenance of a stimulus amplitudesufficient to depolarize axons. Furthermore, the treatment duration neednot be applied continuously for the entire treatment duration so long asa total time of treatment is equivalent to the optimal stimulationduration. For example, if the electrode apparatus needs to be movedduring a surgical procedure, the end-user has the ability to pause thetreatment using a user-operable control as outlined previously. Whenpaused, the system will stop delivering electrical stimulus output andonly resume when the pause control is used again. In this specificexample, once treatment has been applied for 1 hour, the previouslydescribed indicators may notify the user of treatment completion.

In some arrangements, it may be advantageous to deliver multiple boutsof brief electrical stimulation with each bout comprising of thepreviously described durations (e.g., 10 to 90 minutes) and stimulusparameters. The timing between subsequent bouts of brief electricalstimulation, or rest periods, may vary from multiple bouts per day to asingle bout separated by one or more days and delivered on one or moredays. In some embodiments, a single bout of brief electrical stimulationof injured axons transiently upregulates regeneration associated genesand neurotrophic factors in the cell bodies of the injured axons. It isthe intention, according to some embodiments, that multiple bouts mayprolong, transiently increase, or maintain the upregulated expression ofthese genes and neurotrophic factors.

The number of bouts to be delivered may vary depending on the distanceof type of nerve injury. By way of example, a proximal injury in theshoulder may require a minimum of 450 days for injured axons toregenerate from the site of injury to distal muscle in the hand. In ascenario where daily stimulation is provided, delivering multiple boutsof stimulation would require at least 450 bouts in this scenario.Injuries more distal, such a laceration of the digital nerve in thehuman finger, may require considerably less bouts, for instance 30-60,in the case of daily stimulation. The number of bouts delivered isinjury dependent and cannot be determined apriori. In some cases, only afew bouts are needed as repeated bouts may not be beneficial. Theprimary effect of stimulation is to enhance nerve outgrowth across aninjury site and thus after a certain number of days all injured axonshave crossed the injury site and may not benefit from furtherneuroregenerative treatment. Additional benefits of neuroregenerativetherapy is the ability to reinnervate more tissue. In some embodiments,not only does this lead to greater function but also a diminishedpotential for developing chronic pain as regenerating axons are able toreconnect to tissue leaving less free axon ends that could potentiallyform neuromas or cause pain.

In some embodiments, implementation of multiple bouts of briefelectrical stimulation may require modification of the previouslydescribed systems and devices. In one example, a second stimulationsystem that interfaces with the connector 186 on the adhesive patch 80may be programmed to monitor, track, or verify if appropriate treatmentduration and number of treatments have been performed. In someembodiments, the second stimulation system may save patient information,such as a unique identifier, in order to track patient compliance withthe treatment.

In another example, the adhesive patch 80 can be configured with anenergy source to last for the duration of the delivery of multiplebouts. In such an embodiment, the adhesive patch 80 may comprise ofelements allowing it to function as both a validation energy source andstimulation energy source. Additional elements that may be included inthe adhesive patch are an indicator or user controls for adjustingstimulus parameters as mentioned herein.

In some embodiments, the adhesive patch includes circuit elements usedfor wireless communication with an external device or implanted deviceor a combination thereof. In one example arrangement, such device mayinclude a smart phone or other computing device (e.g., tablet). In suchan application, said smart phone may include a software application usedto change stimulation parameters and verify appropriate treatmentduration and application. In another example, such device may include animplanted electrode lead. In such an application, the electrode lead mayinclude hardware and circuitry to communicate with patch and performdesired functions, like electrical stimulation.

Pain Management

In other embodiments, systems (and methods related thereto) may bemodified to not only deliver multiple one or more bouts ofneuroregenerative therapy, but also to deliver pain management therapy.Such a pain management therapy may be delivered immediately beforeand/or after neuroregenerative therapy. Further, the delivery of suchpain management therapy can occur before, during and/or after nerverepair surgery, as desired or required. However, the delivery of energyfor pain management therapy is not limited to this window and may beprovided at a fixed time from delivery of neuroregenerative therapy.Fixed time may represent minutes to hours to days from delivery ofneuroregenerative therapy (e.g., 0-10, 0-30, 0-60 minutes, 0-1, 0-2,0-3, 0-4, 0-5, 0-6, 0-12, 0-12, 0-24 hours, 0-1, 0-2, 0-3, 0-4, 0-5,0-6, 0-10, 0-20, 0-30 days, more than 30 days, any time period withinthe foregoing ranges, etc.). The delivery of energy for pain managementmay also take place when a patient is feeling pain related to the nerveinjury without the need for a fixed delivery schedule.

According to some embodiments, pain management therapy comprisesstimulation in the 50 to 200 Hz range (e.g., 50-60, 50-55, 55-60, 52-58,50-100, 50-200, 50-150, 100-150, 100-200, 70-130, 80-120, 60-120,150-200 Hz, values between the foregoing ranges, etc.). In somearrangements, the frequency of stimulation for reducing pain may be from20 KHz to 500 KHz (e.g., 20-500, 20-100, 50-100, 100-200, 100-300,100-400, 100-500, 200-400, 200-500 KHz, frequencies between theforegoing ranges, etc.) or 1 KHz to 10 KHz (e.g., 1-10, 2-8, 4-6, 3-7,1-5, 5-10 KHz, frequencies between the foregoing ranges, etc.). In someembodiments, the systems can be designed and otherwise configured to(and thus, the corresponding methods involving such systems can beconfigured to) provide an optimal, efficient and/or comfortablefrequency for reducing pain. In some embodiments, the frequencydelivered by the system can be configured to modulate the stimulationenergy being delivered for reducing pain (e.g., according to aparticular patient or other subject, during a procedure for a particularpatient or subject, to target specific types of pain, etc.), as desiredor required. However, in other embodiments, the stimulation energy beingdelivered by the system for reducing pain can be fixed.

In some arrangements, a single bout or treatment round ofneuroregenerative therapy may be sufficient to enhance tissuereinnervation leading to a reduction of the potential for developingchronic pain or other types of long-term pain. However, short term painmay still exist and persist as nerve tissue is regenerating. Any of thesystems described herein may be used to deliver continuous orintermittent pain management therapy after one or more bouts ofneuroregenerative therapy.

FIGS. 31, 32, 33 and 34 depict flow diagrams of embodiments of steps fordelivering neuroregenerative and pain management therapy to a subject.These flow diagrams illustrate various configurations in time thatdelivery of neuroregenerative therapy and pain management therapy can beapplied. While these flow diagrams present some examples ofconfigurations in time of the delivery of these therapies, practitionersor users of the device may opt to bypass or not perform one or moresteps, may substitute alternative steps for depicted steps and/or mayinclude additional steps, as desired or required. For example, apractitioner may opt to perform only one application orneuroregenerative therapy, but multiple applications of pain managementtherapy. Thus, under such circumstances, a practitioner may omit stepswhere additional neuroregenerative therapies can be applied.

FIG. 31 schematically summarizes one embodiment of a procedure, protocolor method for delivering neuroregenerative and pain management therapyto a subject. As shown, neuroregenerative stimulation can be applied 502to the subject in accordance with one or more of the variousarrangements disclosed herein or the like. In the illustratedarrangement, neuroregenerative stimulation is applied 502 after nervesurgery is initially performed 500. However, as shown in connection withother embodiments disclosed herein (see, e.g., FIGS. 32 to 34)neuroregenerative stimulation can be initially applied before nervesurgery is performed, as desired or required. Once the delivery ofneuroregenerative stimulation is complete 504, pain managementstimulation can be applied 506 to the subject. Pain managementstimulation can be applied using any of the devices, systems and/ormethods disclosed herein.

With continued reference to FIG. 31, once pain management stimulation tothe subject is complete, the practitioner can determine if additionalpain management therapies are desired or required 510. Likewise, once ithas been determined that additional pain management therapies are notdesired or required, the practitioner can determine if additionalneuroregenerative therapies are desired or required 512. If neither ofthese additional therapies are desired or required, the protocol,procedure or method can be terminated 514. If, however, additionaltherapies are desired or required, as shown in FIG. 31, the practitionercan choose to repeat one or more of the steps, as desired or required.

FIG. 32 schematically summarizes another embodiment of a procedure,protocol or method for delivering neuroregenerative and pain managementtherapy to a subject that is similar to the one illustrated in FIG. 31.However, in FIG. 32, neuroregenerative stimulation is applied 520 priorto performing nerve surgery 524. In FIG. 32, nerve surgery is performed524 prior to applying pain management stimulation 526. However, in theprocedures schematically illustrated in FIGS. 33 and 34, nerve surgery548 is performed after the application of both neuroregenerativestimulation 540 and pain management stimulation 544. In FIG. 33, theapplication of neuroregenerative stimulation 540 occurs prior to theapplication of pain management stimulation 544. Alternatively, however,in FIG. 34, the application of pain management stimulation 560 occursprior to the application of neuroregenerative stimulation 566.

According to some embodiments, the pain management therapy may bedelivered concurrently with neuroregenerative therapy. That is, inbetween successive pulses in the neuroregenerative paradigm 600, a painreducing waveform 602 may be delivered. Such waveforms may includesinusoidal, rectangular, ramped and/or any other scheme, pattern orshape. By way of example, FIG. 35 illustrates a 1 KHz sine waveinterspersed with biphasic 20 Hz rectangular neuroregenerative pulses.However, any other wave/pattern, frequency and/or other properties canbe used with respect to the delivery of stimulation energy, as desiredor required.

In some embodiments, the existing of a percutaneously placed lead andelectrode already interfaced with an injured nerve provides a uniqueadvantage to providing one or more follow-up stimulation energy forreducing pain. Thus, the requirement for a separate procedure to gainaccess to nerve tissue (and/or the surrounding anatomical region) forthe delivery of stimulation energy for pain management is not necessary.This is important as the site of neuropathic pain would be the site ofnerve injury. Other advantages include the ability to validatetherapeutic efficacy of the pain management therapy, the ability totitrate stimulus levels to produce optimal or enhanced pain managementthrough recording of biological signals and/or the like.

In some embodiments, as illustrated in FIG. 36, a system that deliversneuroregenerative therapy (e.g., in accordance with any of thearrangements disclosed herein or equivalents thereof) comprises aseparate actuator, button, control, controller and/or other device,feature or component to help deliver pain management therapy. In someembodiments, such a feature or component can be incorporated into one ormore other features, components, devices and/or portions of the system.In other arrangements, a separate system 610 can be used to deliver painmanagement therapy and can also include a control and indicator 612. Insome embodiments, such a separate control is enabled or is otherwiseconfigured to be activated and/or controlled by a patient, caregiver,medical professional and/or the like, as desired or required.

In some embodiments, once neuroregenerative therapy is complete, thesystem is configured to only deliver pain management therapy. In otherembodiments, both neuroregenerative and pain management therapies areavailable (e.g., intermittently, indefinitely, for a specific timeperiod, until a particular event or threshold is attained, as otherwisedetermined by the system, directed by the practitioner or other userand/or as dictated by one or more other factors or conditions).

In some embodiments, a separate device or system can be configured toreplace a device that delivered neuroregenerative therapy.Neuroregenerative delivery devices, as described herein, can be deployedor otherwise activated at the time or immediately after surgery torepair an injured nerve. For example, pain management therapy, on theother hand, can be performed in home settings or typically performed insettings away from a medical environment (e.g., hospital, clinic,doctor's office, etc.). Therefore, it may be advantageous, under certainembodiments, to change or swap the neuroregenerative device with a painmanagement device that interfaces the electrode 250 that has alreadybeen placed upstream from the incision site 614 and interfaced with theinjured nerve.

According to some embodiments, in cases of neuroregenerative therapyand/or pain management therapy, the corresponding system can be a bodyworn wearable and directly adhere to a limb 616. In some embodiments,the same device or system can be used to deliver both theneuroregenerative therapy and the pain management therapy. In otherarrangements, different systems can be used to deliver neuroregenerativetherapy and pain management therapy. Regardless if the same or differentstimulation energy delivery devices or systems are used forneuroregenerative therapy and pain management therapy, such devices orsystems can be body worn (e.g., directly or indirectly attached to asubject) or not body worn, as desired or required by a particularapplication or use.

In some embodiments, a control (e.g., device, system, component,feature, etc.) to enable, execute or otherwise facilitate painmanagement is triggered or otherwise initiated using a separate device(e.g., a remote device) 618, such as a smartphone or otherradiofrequency (RF), Bluetooth and/or other wireless/wired transmittingenabled remote. In the example of a smartphone or other computing deviceused to enable pain management therapy, such a smartphone or otherdevice may also be configured to manage or otherwise control managementof a desired or required therapy through an application (e.g., asmartphone application or program) and include information such asrecording delivery times, amount of energy delivered, compliance withtherapy, targeted levels of stimulation, deviations over time fromstimulation targets, etc. In some arrangements, no physical controls arefound on the pain management system and it is strictly controlledthrough software found on a computer, tablet, smart phone, etc. Saidsoftware may adjust stimulation parameters, time of therapy, deliverytimes, communication with physicians, etc.

In some embodiments, the system used to deliver pain management therapyor neuroregenerative therapy, may include a battery or similar powersource. In other arrangements, the system includes a wireless chargetransfer mechanism (e.g., inductive coupling coils or electromagneticcoupling circuitry) that may be used to power the device. In someembodiments, wirelessly transferred power 620 coming from a computingdevice such as a computer, tablet, smartphone, other computing deviceand/or the like can be configured to provide power (e.g., toelectrically charge) to a charge storage device such as a capacitor(e.g., a super capacitor). In some embodiments, a super capacitorconfigured to be charged in this manner can be configured to beprogrammatically charged to deliver set amounts of pain management orneuroregenerative therapy. In some embodiments, a super capacitor inconjunction with a battery may be used to reduce the voltage drop of thebattery due to high current consuming events (e.g. transmitting datawirelessly). For example, in some arrangements, set amounts may includepreset amount of charge delivered, time durations, stimulus settings,etc. In some arrangements, a near-field communication protocol utilizingan unlicensed frequency band, such as, by way of example, 13.56 MHz, canbe used to transfer power and/or data to and/or from the pain managementdevice or system. However, any other configuration can be used tofacilitate the transfer of power and/or data to and/or from the painmanagement device or system, as desired or required.

In some embodiments, the computing device/tablet/smart phone may alsopose as a payment system. In such arrangements, the computing device mayunlock or enable pain management therapy once a payment has beenreceived.

Shapeable Electrode Lead—Generally

Nerve injuries can occur in various parts of the body and are usuallyunpredictable. Surgical repair of these injuries typically involves anopen incision or open surgical area. Interfacing (e.g., reaching,contacting, accessing, getting close to, etc.) a nerve to deliverneuroregenerative therapy in these scenarios can involve using anelectrode (e.g., a cuff style electrode). However, typically, knownelectrodes (e.g., cuff style electrodes) are not able to be removedpercutaneously and are only suitable for the duration of a surgicalprocedure or they are implanted permanently. Given the general transientnature of neuroregenerative therapy, having a nerve interface that canappropriately contact the nerve in an open surgical scenario, such asfor nerve repair, and be subsequently removed (e.g., seamlessly, withoutthe inclusion of additional surgical procedures, etc.) from the body ofa subject can be important and helpful for the advancement and/oradaptability of such therapies. Additionally, the use of a shapeableelectrode that can be easily withdrawn is advantageous in the deliveryof pain management therapy following nerve repair as described herein.

In some embodiments, percutaneously-placed electrodes may be suitablefor the delivery of neuroregenerative therapy and/or pain managementtherapy. In some embodiments, the electrode lead may be shaped toconform to the specific anatomical area in which it will be placed.Advantages and benefits of a shapeable aspect of the electrode leadinclude, without limitation, the ability for the electrode lead tobetter conform to a region of the anatomy, allowing placement of theelectrode lead along trajectories not parallel to the longitudinal axisof a target nerve, ability to at least partially wrap around and/orotherwise at least partially surround a target structure and maintainposition, ability to create a shape used to avoid anatomical structureswhile still engaging the target nerve, ability to place electrode leadnear target nerve without having to rely on surrounding connectivetissue for anchoring, ability to withdraw electrode without damaging arepaired target nerve, better localize the treatment to a desired sitewhich may reduce current density needed to elicit treatments (e.g.neuroregenerative and/or pain management therapy), relieve or preventpain, discomfort, or trauma that might otherwise be caused byinflexible, stiff, or protruding implanted materials, etc.

According to some embodiments, any of the configurations disclosedherein, or equivalents thereof, can include an electrode lead that hasone or more portions that are shapeable. In some arrangements, only aportion of the electrode lead is shapeable (e.g., includes a shapeableaspect). However, in other embodiments, the entire electrode lead isshapeable.

The surgical area or area that includes and/or surrounds the targetedinjured nerve may have undergone sufficient trauma such that it does notresemble standard anatomy (e.g., structural, material changes may haveresulted). Moreover, having a shapeable aspect of the electrode lead canbe advantageous in cases of open surgery, as the lead may be shaped toconform (e.g., generally, approximately, automatically, manually, etc.)to a particular nerve irrespective of the anatomical landscape. In somearrangements, the shaping of one or more portions of the lead body orassembly 1100 (e.g., the distal aspect 1102 and/or the proximal aspect1104) may be performed by hand, as depicted in FIG. 37A. In someembodiments, such manual shaping or manipulation can be accomplishedusing one or more surgical instruments (e.g., forceps), as shown in FIG.37B, by robotic equipment and/or the like. In other embodiments, nosurgical instruments, equipment and/or the like are used. In someembodiments the shaping is performed, at least in part within thesurgical area. For example, the electrode lead body 1100 can be shapedeither entirely or partially once the lead body 1100 has been positionedwithin the targeted surgical area, as desired or required. As discussedherein, in some embodiments, the proximal portion or aspect of the leadbody or assembly 1100 can be configured to be rigid or substantiallyrigid to permit the proximal portion or aspect to be inserted into astimulation device or other device (e.g., directly, without the need fora separate coupler or member, etc.). In some embodiments, the rigidityof the proximal portion is greater than the rigidity of the distalportions of the lead.

For example, the ratio of the rigidity of the proximal portion to therigidity of one or more portions that are distal to the proximal portion(e.g., the distal end) is at least 5:1, 15:1, 10:1 or 20:1 (e.g., atleast 5:1, at least 10:1, at least 20:1, at least 50:1, at least 100:1,at least 150:1, at least 200:1, at least 300:1, at least 400:1, at least500:1, at least 1000:1, at least 1500:1, at least 2000:1, at least2500:1, at least 3000:1, at least 4000:1, at least 5000:1, at least7500:1, at least 10000:1, at least 15000:1, at least 20000:1, at least25000:1, at least 30000:1, at least 35000:1, at least 40000:1, at least45000:1, at least 50000:1, 5:1 to 10:1, 10:1 to 15:1, 15:1 to 20:1, 20:1to 50:1, 10:1 to 50:1, 50:1 to 100:1, 10:1 to 100:1, 100:1 to 500:1,100:1 to 1000:1, 100:1 to 2000:1, 100:1 to 3000:1, 100:1 to 4000:1,100:1 to 5000:1, 100:1 to 6000:1, 100:1 to 7000:1, 100:1 to 8000:1,100:1 to 9000:1, 100:1 to 10000:1, 100:1 to 15000:1, 100:1 to 20000:1,100:1 to 25000:1, 100:1 to 30000:1, 100:1 to 35000:1, 100:1 to 40000:1,100:1 to ratios greater than 40000:1, values or ranges within or betweenthe foregoing, etc.), as desired or required.

In some embodiments, the ratios and/or other relative measurements ofrigidity discussed herein (e.g., in the preceding paragraph) relate toYoung's modulus values or coefficient of stiffness. However, in otherembodiments, the above ratios can relate to any other quantitativemeasure of rigidity or stiffness. In some embodiments, the rigidity orstiffness data provided herein are for the entire relevant portion orsection of the lead assembly (e.g., the proximal end, the most distalportion, one or more portions that are distal to the proximal portion,etc.). Thus, such measurements of rigidity or stiffness can include theimpact of all components of the lead assembly and the generalconfiguration of the particular lead assembly section (e.g., includingouter layer or covering, electrodes, contacts and/or other electricalcomponents or devices, inserts, wires or other electrical conductors,coverings or coatings, etc.). However, in other embodiments, therigidity of stiffness ratios and/or other data provided herein (e.g.,relative data) can pertain only to one or more of the components of thelead assembly along a particular section or portion. For instance, theratios can apply to the most rigid or stiff component (e.g., theproximal insert, the distal insert, any other insert, etc.) of theassembly along a particular portion or section.

In some non-limiting examples, rigidity along the proximal portion orsection of the lead assembly (e.g., the most proximal portion that isconfigured to directly secure to a stimulation device), as measured bythe Young's modulus (e.g., for entire section or portion as a compositethat includes all components and/or other member, for only the mostrigid or stiff member (e.g., insert), etc.), can be 100 to 250 GPa(e.g., 100, 150, 200, 210, 220, 230, 100 to 200, 200 to 250, 200 to 220,200 to 230, 210 to 230 GPa, values within and between the foregoingvalues or ranges, etc.). Further, rigidity along one or more distalportions or sections of the lead assembly (e.g., the most distal sectionor portion of the assembly, one or more sections or portions that aredistal to a more stiff or rigid proximal portion, etc.), as measured bythe Young's modulus (e.g., for entire section or portion as a compositethat includes all components and/or other member, for only the mostrigid or stiff member (e.g., insert), etc.), can be 0.01 to 0.05 GPa(e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.01 to 0.05, 0.01 to 0.04, 0.01 to0.03, 0.01 to 0.02, 0.02 to 0.05, 0.02 to 0.03, 0.03 to 0.05, 0.03 to0.04, 0.04 to 0.05 GPa, values within or between the foregoing values orranges, etc.). In such a configuration, the ratio of rigidity (e.g.,based on Young's modulus) between proximal and distal sections orportions of the assembly is 2000:1 to 25000:1 (e.g., 2000:1 to 25000, atleast 2000:1). However, in other embodiments, the Young's modulus and/orthe relative rigidity ratios can be higher or lower than the valuesindicated above, as desired or required by a particular use orapplication.

Shaping can include the application of force to the electrode leadresulting in a change in shape of the lead. Ceasing or changing theforce can result in the electrode lead maintaining the shape that wascreated with the applied force.

For any of the embodiments disclosed herein, a lead can include thenecessary structure, components and/or design in order to be able tomaintain the shape that is provided to it (e.g., by a surgeon or otherpractitioner) during use. For example, the lead can be configured tomaintain a particular shape provided to it by a surgeon (e.g., usingforceps) until another external force is imparted upon it. Such externalforces can include, without limitation, a force created by the surgeon,a force created by encountering an anatomical structure (e.g., tissue)while the lead is being manipulated and/or the like.

According to some embodiments, a lead is configured to maintain theshape provided to it with no or relatively minor resilient forcesattempting to have the lead otherwise revert to its original shapeand/or some other steady-state shape. Such resilient forces can resultfrom the materials used in the lead and their physical properties, theconfiguration of the lead and/or the like. In certain examples, onceshaped in a desired orientation or manner, the lead is configured so themaximum it moves or reshapes (e.g., due to resilient forces associatedwith its design and configuration) is 0% to 5% (e.g., 0 to 5, 1 to 5, 2to 5, 3 to 5, 4 to 5, 0 to 4, 1 to 4, 2 to 4, 3 to 4, 0 to 3, 1 to 3, 2to 3, 0 to 2, 1 to 2, 0 to 1, 0 to 0.10, 0.10 to 0.25, 0.25 to 0.5, 0.5to 0.75, 0.75 to 1, 0 to 0.25, 0 to 0.5%, values or ranges between theforegoing, etc.). In other arrangements, once shaped in a desiredorientation or manner, the lead is configured so the maximum it moves orreshapes (e.g., due to resilient forces associated with its design andconfiguration) is greater than 5% (e.g., 5 to 10, 10 to 20, 5 to 20%,values or ranges between the foregoing, greater than 20%, etc.).

As noted above, once shaped or reshaped, a lead, according to any of theembodiments disclosed herein, can be configured to maintain orsubstantially maintain its shape (e.g., until re-shaped). In someembodiments, assuming external forces are imparted (e.g., directly orindirectly) on the lead, the lead can maintain the shape provided to itfor a time period that is greater than 0.01, 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4 or 5 seconds. In other configurations,such a time period is at least 0.01 to 10, 0.01 to 20, 0.01 to 30seconds, 0.01 seconds to 1 minute, 0.01 seconds to 2 minutes, greaterthan 2 minutes, etc.). Accordingly, since a lead is able to maintain itsshape (e.g., with no or relatively small movement after shaping) for aminimum time period, the lead can be shaped to strategically surroundand/or be adjacent to a desired anatomical structure (e.g., a targetednerve) and maintain such a shape and orientation (e.g., relative to theanatomical structure) for the duration of a procedure, as desired orrequired.

In some embodiments, the lead does not include any braids, coils and/orother reinforcement members. For example, many catheters, tubing andother intraluminal devices include braids, coils or other such featuresor components in order to provide the necessary strength, pushability,flexibility, torquability and/or other desired properties withoutkinking or other undesirable deformations. In contrast, however, in someembodiments, any of the lead assemblies disclosed herein can beconfigured to not include any reinforcing members or features (e.g.,braids, coils, etc.). This can permit the lead to be shaped or re-shapedin a manner that allows the lead to maintain its shape for a minimumtime period (e.g., greater than 1, 5 or 10 seconds, etc.) and/or for aduration of a procedure or step of a procedure.

Further, according to some embodiments, any of the lead assembliesdisclosed herein can be manufactured and/or otherwise assembled orconfigured to be advanced through a portion of the anatomy (e.g.,subcutaneously to and/or from an injury site, a surgical incision, etc.)without the need of needle or other rigid member. Therefore, in somearrangements, the lead assembly includes the desired strength, rigidityand/or other physical properties to overcome resistive (e.g., blocking,frictional, etc.) forces encountered when tunneling the lead throughanatomical tissue. These embodiments are in contrast to otherpercutaneous leads commercially available that require a tool (needleassembly, guiding catheter, etc.) paired with the lead assembly to reachthe target anatomy. Such lead assemblies are typically extremelyflexible and may be prone to fracturing.

As shown in FIG. 38A, according to some examples, shaping may includecreating a curved element of the distal aspect 1102, which may includeconductive elements 1108, that deviates from the longitudinal axis 1106of the electrode lead body 1100. In other examples, shown in FIG. 38B,shaping may be used to give the electrode lead body 1100 a generallyhelical shape. As illustrated, such a shape can be configured tosurround a targeted nerve structure 1110.

For any of the embodiments disclosed herein, the ability for a portionof the electrode lead body 1100 (e.g., the distal aspect 1102) to holdits shape can be advantageous so that the electrode can more predictablyand securely contact the nerve structure 1110 and maintain that contact(e.g., similar to a cuff electrode yet with the flexibility to beremoved atraumatically).

In yet another configuration, as depicted in FIG. 38C, shaping of anelectrode lead body 1100 may be used to create one or more U-shapedportions. Only a few examples of shaping, the ability to shape theelectrode have been illustrated and otherwise disclosed in the presentapplication. It should be understood that selectively shaping of anelectrode lead body 1100 may result in a myriad of shapes, includingshapes that are not discussed within the present application, to be ableto conform to any anatomical scenarios encountered and/or satisfy anyother goal or purpose.

Existing devices can include one or more limitations and/or otherdisadvantages vis-à-vis embodiments disclosed herein. For example, incardiac applications, catheter type electrode leads are often used topace the heart (e.g., provide electrical stimulation or other energy toheart tissue), record signals from the heart and/or the like. Anyshaping of the distal aspect of these catheter type leads can occurprior to placement within the body. Manufacturers typically producevarious models having distal aspects (and/or other portions) thatinclude different shapes. Such varying models can be selected based onone or more factors, such as, for example and without limitation, theinsertion method that is used to enter the subject's anatomy (e.g.,femoral or radial artery access), one or more characteristics of thesubject's anatomy (e.g., whether the subject's aorta is narrow or wide).Furthermore, such prior shaping technologies are not limited tocatheters with electrodes, but can also include guidewires, guidecatheters or more generally devices that must traverse through asubject's vasculature or other intraluminal anatomical network.

In the neurosurgical field, electrodes used to interface the brain(e.g., deep brain stimulating electrodes) or the spinal cord (e.g.,spinal cord stimulation electrodes) are presently placed under imageguidance to ensure localization with high precision. These proceduresare minimally invasive and do not require open surgery. Under suchcircumstances, electrodes are not shapeable, but are insteadsufficiently flexible to be compliant with the tissue they interface(e.g., brain or spinal cord). A stylet, metal insert or other device istypically used for placement of these leads in order to provide therequisite stiffness, pushability and/or other properties within thetissue. Removal of the stylet can allow for the surrounding tissue toexert forces on the lead to keep it in place. However, withoutsurrounding tissue, the flexibility of the lead may not allow it to beshaped and used in the context of peripheral nerve repair where therepair procedure is typically performed in an open surgical area (e.g.,or minimally invasive). The ability to shape the lead to the specificanatomical area (e.g., during a surgical procedure) is not possible withexisting technologies.

In some embodiments, the electrode lead may include one or moreconductive elements 1108 distributed along one or more portions of thelead (e.g., the distal aspect of the lead). In other arrangements, theconductive elements 1108 are positioned along the length of the lead,either in lieu of or in addition to being at or near the distal end ofthe lead, as desired or required. The conductive elements can includedifferent shapes, sizes and/or other characteristics, as desired orrequired. For example, as illustrated in FIG. 38A, the conductiveelement 1108 at the distal end of the electrode lead body 1100 may beshaped in a manner to cap the electrode lead body 1100 and also providea larger surface area that may be used to provide stimulus current totissue such as peripheral nerves. With continued reference to FIG. 38A,a second conductive element 1108, positioned away from the tip element,can be shaped as a ring with said ring varying in width from 0.05 to 5mm (e.g., 0.05-0.06, 0.06-0.07, 0.07-0.08, 0.08-0.09, 0.09-0.1, 0.1-0.2,0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1,1-2, 2-3, 3-4, 4-5 mm, ranges between the foregoing, etc.) and/or can bephysically coupled to a conductive insulated wire 1122 (e.g., directlyor indirectly). In some arrangements, at least two conductive elements1108 are used to create a bipolar stimulating field. A plurality ofconductive elements can also form an electrical stimulation arrayallowing to shape or otherwise modify or impact the current field.

According to some embodiments, the orientation of the anode and cathodediffer from traditional orientations or configurations. For example andmore specifically, in cardiac applications with bipolar electrodeconfigurations, the cathode can be in the distal most electrode. In somearrangements, the shapeable lead with multiple conductive elementscomprises a distal anode and a proximally placed cathode (e.g., theopposite of a traditional cardiac pacing electrode). Such aconfiguration may be advantageous in the delivery of neuroregenerativetherapy as one mechanism of action for this therapy is the conduction ofaction potentials proximally towards the cell body. In some embodiments,when the lead is placed upstream or proximal to the nerve injury site, aresulting electrical field may depolarize the target nerve and causeaction potentials to travel proximally towards the cell body. If theelectrode configuration is traditional (distal cathode, proximal anode)there is a risk that at higher stimulation amplitudes anodal block mayoccur resulting in a blocking of conducting action potentials and apotential decrease in therapeutic efficacy. Reversing the configuration(distal anode, proximal cathode) obviates this situation. This holdstrue only when an electrode lead is inserted into the patient from aproximal to distal trajectory.

In some embodiments, the spacing between the cathode and anode in abipolar configuration may be large enough to span a site of nerveinjury, such distances between anode and cathode may include 3 to 50 mm(e.g., 3 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 10 to 50, 20 to50, 30 to 50, 3 to 20, 5 to 20, 10 to 40, 10 to 30, 20 to 50, 20 to 40,30 to 50 mm, values or ranges between the foregoing ranges, etc.).

According to some embodiments, such configurations include a distalanode and a proximal cathode such that the cathode is situated proximalto the site of injury. This can allow action potentials to travelunimpeded (or substantially unimpeded) towards the cell body fortherapeutic efficacy. Another advantage of such a configuration is thatthe electrical field resulting from the electrodes spanning the injurysite can, in some embodiments, further provide a neuroregenerativeeffect through other mechanisms of action. In some arrangements, this isknown that Schwann cells, Macrophages, and other support cells in thevicinity of the nerve injury site are responsive to electrical fieldgradients and these may in turn further facilitate neuroregeneration.

In some embodiments, the electrode lead body 1100 with multipleconductive elements 1108 (e.g., as described herein) is coupled (e.g.,physically, electrically, operatively, directly, indirectly, etc.) to astimulation source that can include circuitry to test the connectivityand placement of the electrode lead. In some arrangements, thestimulation source can also be configured to provide neuroregenerativetherapy (e.g., via the delivery of stimulation energy). In otherarrangements, the stimulation source can also be configured to providepain management therapy (e.g., chronic pain management by electricalstimulation).

In some embodiments, the electrode lead comprises a circular or curvedshape (e.g., at least a partial circular or curved shape) and comprisesan outer diameter (or other cross-sectional dimension) of 0.1 to 5 mm(e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8,0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5, 1-4, 0.5-4, 1-4, 0.1-5, 4-5, 3-5,2-5 mm, ranges between the foregoing, etc.).

In some embodiments, the electrode lead comprises multiple sections(e.g., 2, 3, 4, 5, more than 5, etc.). Each section can include adifferent shape. However, in some configurations, two or more of thesections can include a similar or generally similar shape, as desired orrequired.

According to some embodiments, as depicted in FIG. 39A, thecross-sectional shape of the proximal aspect of the electrode lead maybe at least partially circular, cylindrical and/or otherwise curved,while the cross-sectional shape of the distal aspect may include a thinrectangular shape (or other non-circular or curved shape). In somearrangements, the longitudinal shape may be tapered (e.g., from a largerouter diameter to a smaller outer diameter). In some arrangements, theproximal aspect may be shapeable, allowing the user to have theelectrode lead deviate from the longitudinal course of the nerve, whilemaintaining nerve contact at or along the distal end. However, in otherembodiments, the proximal aspect or portion of the electrode lead canremain circular for its entire length. In some configurations, thecross-sectional shape and size of the lead remains constant orsubstantially constant for the entire or substantially the entire lengthof the lead (e.g., including the proximal portion that is configured tocouple to a stimulation device or other device).

According to some arrangements, the thickness of an electrode lead canvary along its length. For example, the thickness of the lead can bedifferent in one or more sections. The generally flattened rectangularshape, for instance, may be sufficiently thin (e.g., 10 μm to 500 μm) inrelation to the cylindrical component. This may be advantageous as thethin rectangular portion may interface the injured nerve atraumaticallyby being positioned underneath the nerve, while the cylindrical portionfacilitates percutaneous placement or delivery and withdrawal of theinterface via an insertion tool.

In some embodiments, as illustrated, for example, in FIG. 39B, the thinrectangular shape or flap 1112 can be used to anchor or otherwise secure(e.g., temporarily, permanently, etc.) a cylindrical lead throughsurface tension (e.g., using fluids located in and/or around tissue toprovide surface tension with the flap). In some arrangements, the thinrectangular shape comprises one or more flexible (e.g., non-rigid)materials, such as, for example and without limitation, a polymericmaterial, an elastomeric material and/or the like (e.g., siliconerubber, polyurethane, etc.).

In some embodiments, the distal aspect of the electrode lead comprisesone or more materials that may be shaped. In one example, as illustratedin FIG. 40A, the lead is configured to be shaped as a result of, atleast in part, an insert 1114 that may be located within the electrodelead body 1100. Such an insert 1114, in some configurations, may becoupled to a conductive element 1108 placed at the distal end (e.g.,tip) of the electrode lead body. Said assembly may then be covered(e.g., using a layer, coating, jacket, other covering, etc. 1116). Sucha covering can comprise one or more polymeric and/or elastomericmaterials. In one example, the insert 1114 can be conductive (e.g., atleast partially) and act as a wire or other conductor carrying signalsto and from a conductive element.

For any of the embodiments disclosed herein, as depicted schematicallyin the partial longitudinal cross-section of FIG. 40B, an electrode leadassembly 100 can be configured to be shapeable or manipulatable using acombination of: (1) at least one shapeable (e.g., malleable, bendable,etc.) insert or other member 1114, and (2) at least one softer outerjacket and/or other covering 1116. The lead assembly can includeadditional layers, coatings, members, components, features and/or thelike, as desired or required. For instance, the electrode lead caninclude one or more of the following: electrodes, wires or otherelectrical conductors, other electrical components, braiding, otherstructural elements or features, lumens or other passageways and/or thelike.

As used herein, electrical wire and electrical conductor are broad termsand can include, but are not limited to, wires, printed circuit boards,conductive tracks, conductive pads, etched conductive features, solderedconductive features, other electrically conductive features and/or anyother device, member, component or feature that is configured to haveelectrically conductive properties.

With continued reference to the schematic of FIG. 40B, for any of theembodiments disclosed herein, the shapeable insert or member 1114 can beconfigured to maintain its shape after being shaped by a practitioner orother user. Likewise, the electrode lead 1100 that comprises theshapeable insert or member 1114 can be configured to maintain its shapeafter shaping. Shapeable inserts or members 1114, and thus thecorresponding leads or lead assemblies 1100 in which they are included,can be configured to maintain their shape during a procedure. In someembodiments, such leads 1100 can be configured to be re-shaped after theinitial shaping during use (e.g., during the execution of a treatmentprocedure). For instance, a shapeable insert or member 1114 (and as aresult, the entire lead) can be reshaped by exerting a force and/ormoment on one or more portions of the lead. As discussed herein, suchforces can be applied by a practitioner or other user manually (e.g.,using the practitioner's hands) and/or using one or more tools (e.g.,forceps, other surgical instruments or tools, etc.). In another example,the lead assembly may be shaped and/or re-shaped by the normal forcesexerted by the surrounding anatomy. This can be advantageous in at leasttwo scenarios, such as, for example, during long term implantationand/or during a lead removal procedure.

By way of example, during long term implantation (e.g., for painmanagement therapy), forces (e.g., passive forces) exerted on ashapeable insert or member (e.g., by the surrounding tissue and/or otherportions of the anatomy, other sources of force, etc.) can reshape(e.g., continuously reshape) the electrode lead allowing it to conformto the desired location without creating undue tension or stress on theinjured nerve. Also for purposes of illustrated non-limiting examples,during lead removal (e.g., pulling the lead out of the anatomy of asubject) forces (e.g., passive forces) exerted on the shapeable insertor member (e.g., by the surrounding tissue and/or other portions of theanatomy, other sources of force, etc.) can cause the lead to deform, atleast partially (e.g., to a straight line, generally a straight line, asmooth curve, etc.) such that the lead may be removed without kinking,buckling and/or otherwise undergoing deformation that may induce injuryto the surrounding anatomy of the subject.

For any of the embodiments disclosed herein, an insert or other member1114 of the lead assembly 1100 that is configured to facilitate shapingor re-shaping of the assembly can include plastic deformationproperties. In other words, such an insert or other member 1114 can beconfigured for distortion that occurs when a material is subjected tocertain forces or stresses (e.g., tensile, compressive, bending, ortorsion forces or stresses) that exceed its yield strength and cause itto elongate, bend, twist and/or the like. Such a distortion can betemporary, such that the insert or other member can maintain its shapewhen no external forces are exerted on it (e.g., as it sits on a tableor other surface, until a user exerts another bending or otherre-shaping force or moment, etc.). In some arrangement, when theelectrode lead is handled (e.g., in mid-air with the distal shapeableaspect unsupported or otherwise not impacted by other external forces),the force of gravity is not sufficient to shape the lead with the leadbeing sufficiently rigid to maintain the desired shape.

For any of the embodiments disclosed herein, an outer jacket or otherouter covering 1116 of the lead assembly 1100 can include elasticdeformation properties. In other words, such an outer jacket or coveringcan be configured to undergo a temporary change in shape once a force isexerted on the lead assembly, and thus the outer jacket or covering.Such members with elastic deformation properties are configured toreassume their original shape or orientation (e.g., are at leastpartially self-reversing) once the force or moment is removed orreduced. For example, an extruded polymeric tube used as an outer jacketis typically extruded in a lengthwise manner (e.g., the length of thetube is greater than the diameter or other cross-sectional dimension).In some arrangements, the tube is configured to maintain the extrudedconformation when forces are applied (e.g., in a perpendiculardirection) to the longitudinal axis of said tube. Such a characteristiccan help account for the elastic recoil of the tube back (e.g.,completely, substantially completely, partially, etc.) to the originalconformation when a force is applied. Plastically deforming of the tubecould require stretching the tube beyond its yield strength.

In some embodiments, as illustrated schematically in FIG. 40B, a gap orspace 1115 exists between the insert or other member 1114 and the outerjacket or covering 1116. In one arrangement, the gap does not includeany materials. However, in some configurations, one or more intermediatelayers or members (not shown in FIG. 40B) are located within the gap orspace 1115. In other arrangements, the insert or other member 1114 isconfigured to at least partially contact the outer jacket or covering1116, as desired or required. Thus, in some embodiments, there is no gapor space between the insert 1114 and the outer jacket 1116.

For any of the embodiments disclosed herein, a shapeable lead assembly1100 can be configured to not include any lumens or other interioropenings. However, for any of the embodiments disclosed herein, ashapeable lead assembly 1100 can be configured to include one or morelumens or other openings. In some embodiments, a shapeable lead assembly1100 does not include any shapeable tubes and/or other at leastpartially hollow (e.g., non-solid) members. In some embodiments, thelead assembly 1100 comprises at least one insert or interior member 1114that at least partially assists with the bending of the assembly andmaintaining the shape of the assembly 1100 once it has been shaped orotherwise manipulated.

For any of the embodiments disclosed herein, the lead assembly 1100 canbe configured to be shaped and/or reshaped during a treatment procedure(e.g., a neuroregenerative procedure). A practitioner or other user canshape or re-shape an insert once a procedure has commenced. For example,the configuration of any of the lead assemblies 1100 disclosed hereincan permit a practitioner to change the shape, direction, orientationand/or the like of the assembly 1100 after it has been inserted withinand/or on a subject. In some embodiments, for instance, a practitionercan manipulate the assembly 1100 to shape or re-shape it to conform tothe anatomy of the subject (e.g., to contact or be in a desiredorientation relative to a nerve, to wrap at least partially around anerve, to abut, secure to and/or otherwise be located near anotheranatomical feature of subject, etc.).

Manipulation can be accomplished by selectively applying forces,pressure, moments and/or any other external influence on one or moreportions of the lead assembly 1100. In some embodiments, as notedherein, such forces or other external influence can be performedmanually (e.g., using the practitioner's hand(s)) using forceps and/orother instrumentation or tools, robotically and/or the like, as desiredor required.

According to some arrangements, the insert 1114 may be coupled to a wireor other conductor that is coupled to a conductive element. In otherembodiments, the insert 1114 may be coupled to a conductive element onone end and a wire or other conductor on the other end that is coupledto a connector. Such material may include various types of metals and/oralloys, such as, for example and without limitation, copper, silvercoated copper, polyimide coated copper, platinum coated tungsten,stainless steel, lead, tin, etc. In some arrangements, the metals may beannealed to soften their structures which may allow them to be shapedwith less force than prior to annealing. In some arrangements the metalmay be incorporated into the distal aspect of the electrode lead as aninsert that may comprise of a rod or cylindrical structure. The lengthof the insert may not be limited to the distal aspect. For example, insome embodiments, the insert spans the entire length of the electrodelead or a majority of the length of the electrode lead (e.g., 50-60,60-70, 70-80, 80-90-90-100, 50-75, 5-90, 60-90% of the length of theelectrode lead, percentages between the foregoing ranges and values,etc.), as desired or required.

In some embodiments, the insert can be coupled (e.g., directly,indirectly, etc.) to a conductive element. The insert can be coupled toa conductive element using any suitable technology or methods,including, for example, resistance welding, laser welding, soldering,crimping, other technologies/methods used to couple metals to oneanother and/or like.

In some embodiments, the lead housing or jacket can comprise one or moreelastic or semi-elastic materials, such as, for example, silicone rubber(e.g., silicone rubber tube), polyurethane, other polymeric materials,other types of elastomeric or rubber materials, other flexible orsemi-flexible materials (PEBAX™, Pellethane™, etc.).

In some embodiments, when force is applied to shape the electrode leadbody 1100, the insert 1114 is configured to undergo deformation (e.g.,plastic deformation). In some examples, the jacket 1116 may also undergosimilar deformation (e.g., plastic deformation) as a result of such anapplication of force. In some embodiments, the jacket may undergoelastic deformation. In such cases, the elastic recoil force of thejacket may be insufficient to overcome the plastic deformation of theinsert resulting in the electrode lead maintaining its shape. In somearrangements, desired shapes are retained until other forces are appliedthat reshape the lead, for example forces resulting from the manualmanipulation or the act of lead removal.

With reference to the schematic illustrated in FIG. 40C, a lead assembly1100 can include a proximal portion or aspect 1104 and a distal portionor aspect 1102. As discussed in greater detail herein, the proximalportion 1104 can be configured to be secured (e.g., directly orindirectly) into a corresponding port of a stimulator or other device orcomponent. As shown in FIG. 40C and discussed with reference to otherarrangements herein, the lead assembly 1100 can include a constant orsubstantially constant outer diameter along its length. In someembodiments, the distal end of the assembly includes a rounded orotherwise tapered shape; therefore, in such configurations, the constantor substantially constant outer diameter applies to only to the lengthof the lead assembly proximal to the beginning of the circular distalend or other tapered configuration of the distal end.

As illustrated in FIG. 40C and discussed in greater detail herein, thedistal portion or aspect 1102 of the lead assembly 1100 can include one,two or more electrodes. Further, as also shown, the proximal portion oraspect 1104 of the assembly 1100 can include one, two or more contactsalong the exterior surface of the assembly. Such contact can helpelectrically couple the electrodes to a stimulation unit or other deviceor component (e.g., once the assembly 1100 has been inserted within acorresponding port or opening of such a device or component).

In some embodiments, as discussed in the present application, theproximal portion or aspect 1104 of the lead assembly 1100 can include astiffer or more rigid configuration than the distal portion or aspect1102 of the assembly. In some embodiments, the distal portion or aspect1102 is further configured to be shaped in a desired configuration. Thelead assembly 1100 can be configured such that the distal aspect orportion and/or other sections or portions of the assembly can maintainsuch a desired shape (e.g., for the duration of a procedure, untilre-shaped or removed, for a minimum time period, etc.), as desired orrequired.

With continued reference to FIG. 40C, the length (e.g., along thelongitudinal or axial direction of the lead assembly) of the leadassembly 1100 can include two or more sections or portions with distinctphysical characteristics. As discussed, in some embodiments, theproximal portion or aspect 1104 can be rigid or stiff relative to one ormore distal portions or aspects 1102. In some arrangements, the sectionC of the proximal portion or aspect 1104 that includes the relativelyrigid or stiff configuration can extend 0% to 10% (e.g., 0 to 2, 2 to 4,4 to 6, 6 to 8, 8 to 10%, values between the foregoing ranges, etc.) ofthe total length of the lead assembly 1100. However, in otherembodiments, the section C of the proximal portion or aspect 1104 thatincludes the relatively rigid or stiff configuration can extend morethan 10% (e.g., 10 to 15, 15 to 20% more than 20%, etc.) of the leadassembly. By way of example, the length of the section C that includesthe relatively rigid or stiff configuration is 30 mm (e.g., for a leadassembly that has a diameter of about 0.05 mm and an overall length ofabout 440 mm).

The portion of the lead assembly 1100 that is less rigid or less stiffthan the proximal section or aspect and that can be configured tomaintain a desired shape can be positioned only along the distal portionor aspect 1102 of the assembly 1100. Thus, in such embodiments, such ashapeable portion of the lead assembly can be located along a distalsection A of the assembly. In some embodiments, such a shapeable, lessrigid portion can extend from the distal end of the assembly to thedistal end of the stiffer, more rigid proximal portion. Thus, in theschematic of FIG. 40C, sections of the lead assembly 1100 denoted bylengths A and B can be identical in configuration and design, allowingthe entire portion of the assembly 1100 distal to section C to be shapedand reshaped, in accordance with the various embodiments disclosedherein. In other embodiments, however, section B can have a different(e.g., greater) stiffness or rigidity than section A of the leadassembly 1100, as desired or required. Further, a lead assembly can beconfigured to include one or more additional sections (e.g., SectionsA′, B1′, B2′) of varying rigidity, stiffness and/or other physicalconfiguration. In some embodiments, as illustrated schematically in FIG.40C, the electrode(s) of the lead assembly are located along the lessrigid or stiff portion while the contact(s) (e.g., which couple theelectrode(s) to a stimulation or other device or component once the leadassembly is coupled to such a device or component) are located along themore rigid or stiff portion.

FIGS. 40D and 40E illustrate longitudinal cross-sectional views of oneembodiment of a lead assembly 1100. As shown, the distal portionincludes an insert 1114 positioned along its interior. In someembodiments, the insert 1114 extend to or near the distal end of thelead assembly. The depicted assembly includes two electrodes 1108 a,1108 b that are separated by a particular distance from one another. Insome embodiments, such a separation distance is 15 mm; however, theseparation distance can be greater or lower than 15 mm, as desired orrequired. Further, in other arrangements, more (e.g., 3, 4, more than 4)or fewer (e.g., 1) electrodes can be included in a particular leadassembly.

With continued reference to FIGS. 40D and 40E, the distal electrode 1108a can include a rounded or tapered distal end. In some arrangements, thedistal electrode extends to the distal end of the lead assembly.However, in alternative configurations, the distal electrode 1108 a maynot extend to the distal end of the assembly. As shown, the electrodescan include any desired shape or configuration (e.g., cylindrical,cylindrical with a domed or cap structure, etc.).

The electrodes 1108 a, 1108 b can be electrically coupled tocorresponding electrical contacts 1109 a, 1109 b along the proximalportion of the lead assembly (e.g., using one or more wires or otherelectrical conductors 1222 a, 1222 b). As discussed herein, the proximalportion of the lead assembly can include a stiffer or more rigidconfiguration. For example, in some embodiments, the proximal portion oraspect includes its own insert 1117. In some arrangements, the insert1117 along the proximal portion of the lead assembly is stiffer or morerigid than the insert along the distal portion. A unitary or segmentedouter covering 1116 can be positioned along the outside of the assembly.In some embodiments, the inserts 1114, 1117 can include one more metalsor alloys (e.g., stainless steel, other steel, copper, brass, etc.).Therefore, for any of the embodiments disclosed herein, the inserts caninclude an outer jacket, cover, coating, layer and/or the like toelectrically insulate the insert from the wires, conductors and/or anyother electrical components of the lead assembly. In some embodiments,such a jacket or covering comprises one or more polymeric materials(e.g., polyimide).

In some embodiments, the lead housing or jacket 1116 can comprise auniform or continuous material thickness throughout the length of thelead body 1100. In some embodiments, the jacket may comprise multipledurometers. For example, as illustrated in FIG. 41, a lower durometermaterial may be used for the distal shapeable aspect 1102 of the leadwhile a higher durometer may be used for the proximal aspect 1104 (e.g.,that may be advantageous in pushing the lead into and advancing itwithin tissue). While such an example outlines two sections with twodurometers, a lead is not necessarily limited to two durometers, but mayinclude multiple segments with varying durometers within or betweensegments.

Under certain circumstances, the durometer of the distal aspect of alead can be 20D to 50D on the shore D scale (e.g., 20D, 25D, 30D, 35D,40D, 45D, 50D, 20D to 50D, 25D to 45D, 30D to 40D, 20D to 40D, 30D to50D, values and ranges between the foregoing values and ranges, etc.),while the durometer of the proximal aspect can be 50D to 80D on theshore D scale (e.g., 50D, 55D, 60D, 65D, 70D, 75D, 80D, 50D to 80D, 55Dto 75D, 60D to 70D, 50D to 70D, 60D to 80D, values and ranges betweenthe foregoing values and ranges, etc.). Thus, in some embodiments, asnoted herein, the hardness, and thus the corresponding durometer, of theproximal aspect of a lead can be greater than that of the distal aspectof the lead, as desired or required.

While the durometer is one parameter that can have an impact (e.g., asignificant impact, under certain circumstances) on the shapeability,functionality and/or other aspects of a shapeable lead assembly, one ormore other properties, such, for example, wall thicknesses ofmaterials/components, can also be impactful (e.g., can be important).

According to some embodiments, a relatively thick outer jacket and/orother covering may require a relatively large amount of force to shapethe lead assembly. For instance, consideration must be given to the factthat such force should be sufficient to also shape the insert positionedwithin the jacket and/or other covering.

By way of example, under certain embodiments, wall thicknesses for thejacket or other outer covering of a lead assembly between 100 and 400 μmcan allow for suitable flexibility of the entire lead assembly (e.g., topermit a practitioner or other user to have the lead assembly assume thedesired or require shape). Thus, in some arrangements, the wallthickness of the jacket or other outer covering of the lead assemblyshould be between 100 and 400 μm (e.g., 100-150, 150-200, 100-200,100-300, 200-300, 150-300, 100-400, 100-500, 200-400, 200-500, 300-500,400-500 μm, values between the foregoing ranges, etc.), as desired orrequired.

In addition, the relation of the wall thickness of the jacket or otherouter covering to the diameter (or other cross-section dimension) of thecorresponding insert can also impact the shapeability and/or otheraspects of the functionality of the lead assembly. For example, in someembodiments, the diameter of the insert is equal to or greater than thewall thickness of the jacket or other outer covering of the leadassembly. For example, the thickness of the jacket or other outercovering can be 100%-500% (e.g., 100-500, 200-400, 100-400, 200-500,300-500, 150-200, 100-150, 100-200, 200-300, 400-500%, percentage valuesbetween the foregoing ranges, etc.) of the diameter of the insert.

Under certain circumstances, while a thickness of the jacket or otherouter covering is greater than the diameter or other cross-sectionaldiameter of the insert, the lead assembly can still achieve the desiredor required shapeability. However, in some embodiments, this can ariseonly if the material of the jacket is relatively soft and pliable. Thus,under such conditions, this can unfavorably reduce the pushability ofthe electrode lead and may result in kinking, an undesirable effect.

In some embodiments, a balance can be struck between the combination ofthe jacket durometer, jacket wall thickness, and insert diameter(assuming a cylindrical structure) to achieve the desiredcharacteristics of a shapeable electrode lead. These desiredcharacteristics may also be chosen to achieve a particular tensilemodulus ratio between varying segments in the lead. For example, theratio of tensile moduli of the proximal aspect to the shapeable distalaspect can be 10 to 20000 or greater (e.g., 10 to 1000, 10 to 100, 100to 500, 500 to 1000, 250 to 750, 300 to 700, 10 to 200, 10 to 500, 100to 20000, 10000 to 20000, 10000 to 30000, 20000 to 30000, 20000 to25000, 20000 to 40000, 30000 to 50000, ratios between the foregoingranges and values, etc.).

In some embodiments, the shapeable component of an electrode lead may beconstructed, at least partially, from and/or with a coiled wire. In somearrangements, the coiled wire spans the length of the lead. In otherarrangements, the coiled wire spans only a portion of the length of thelead. For example, the coiled wire can span only a first length orportion (e.g., the first 10 cm or less, such as, for example, 0-10, 2-8,1-5, 5-10 cm, lengths between the foregoing ranges, etc.) of the lead.However, the extent of the coiled wire need not be limited to thesedistances (e.g., can be greater than 10 cm, as desired or required). Insome embodiments, the coiled wire is physically coupled (e.g., directlyor indirectly) to an electrode. In other embodiments, the coiled wire isnot electrically coupled to any stimulating electrodes. In someembodiments, the coiled wire serves as an electrical connector to othercircuitry located at, along or near the distal end of the lead housing.Depending on the application, required flexibility and memory propertiesand/or other design considerations, the spacing between adjacent coilsis zero (e.g., the coils are touching one another) or is a fixeddistance. In some embodiments, the coiled wire is insulated oruninsulated. In some arrangements, the coiled wire is encased, at leastpartially, in and/or with a flexible jacket or other covering, asdiscussed above. In some embodiments, the coiled wire may act as anelectromagnetic shield, thereby providing at least partial noiseimmunity to wires or circuitry contained within it.

In some embodiments, as shown in FIG. 42A, a multi-lumen extrusion orother design may be used in the lead housing 1118. Thus, in suchembodiments, the lead housing can include two or more lumens extending(e.g., partially, completely) through it. In some examples, as shown inFIG. 42B, one lumen 1120 may be used to house or otherwise receive(e.g., slidably, permanently, temporarily, etc.) an insert 1114, whileother lumens may house wires or other conductors 1122 that connect toconductive elements. In other arrangements, a lumen may be configured toreceive a stylet (e.g., interchangeably) to re-shape or re-position thedistal aspect and/or another portion of the lead housing (e.g., in aperioperative setting).

In some embodiments, a proximal (and/or other) aspect of the lead mayhave properties that enable it to be very flexible. In some embodiments,such flexibility is greater than adjacent or other portions of the lead.In some examples, the flexibility of one or more portions or aspects ofa lead are created using silicone tube or other softpolymeric/elastomeric materials. The flexibility of the proximal portionor aspect of the lead assembly may be advantageous or beneficial in thecontext of external anchoring where the length of electrode lead that isexternal to the body is coiled loosely (e.g., to provide strain relief).Coiling of a flexible tube can permit for less recoil force. High recoilforces can disadvantageously dislodge the electrode lead.

In some embodiments, the flexibility of the proximal portion or aspectof the lead assembly is advantageous or beneficial. For example, such adesign can help prevent or reduce force being transmitted to the distalportion or aspect that contacts, is in proximity to and/or otherwiseinterfaces with the targeted nerve. In one example, movement of theflexible aspect of the lead does not result in the correspondingdisplacement of the distal aspect. This can be largely due to thediffering properties of the proximal and distal aspects as in the casewhere the distal aspect contains an insert that is shapeable. In someembodiments, it is advantageous to not have the distal tip deflect(and/or to limit deflection) when forces are applied proximally, as tipdeflection may interfere with the efficacy of neuroregenerative therapysince the electrodes may no longer interface with the nerve.

In some embodiments, as shown in FIG. 43, the distal aspect may includeone or more dimples, grooves, recesses and/or other features 1124 (e.g.,to facilitate grasping of the lead using forceps and/or other tools). Insome arrangements, the dimple or groove 1124 spans the circumference (orother outer extent) of a cylindrical lead. In other arrangements thedimple or groove 1124 may only partially cover the circumference orother outer extend (e.g., half of the circumference).

In some embodiments, the jacket 1116 of the distal and proximal ends maydiffer in color. In some arrangements, the distal end may have areas ofdiffering color. Colors may indicate differing segments (e.g., aspectsthat are shapeable or not) or may indicate a particular length and maybe useful in positioning of the lead. In some embodiments, the proximalportion may be colored red with a corresponding matching color on thedevice to which the proximal end would connect (e.g., stimulationdevice). In some embodiments, the distal portion can be colored in adifferent color such as blue, purple and/or any other color to clearlydistinguish between proximal and distal ends. This allows the user toquickly, predictably and safely match the lead color to the device colorto minimize confusion about how to connect the lead assembly. In someembodiments, marker bands or arrows may be screen printed or laseretched onto the jacket of the lead assembly. These marker or indicatorsmay aid a user in understanding what end of the assembly to connect witha device or how far to plug in the proximal portion of the lead into thedevice (e.g., the lead should not be inserted past the marker band orthe marker band communicates the extent that the lead inserts into adevice). In some embodiments, line segments corresponding to unitmeasures can be printed on the lead to aid as a ruler.

In some embodiments, the proximal portion or aspect 1104 of theelectrode lead assembly may terminate with a connector. Such a connectormay be a standard medical connector (e.g., manufactured by Redel, Lemu,ODU, etc.). However, the connector can be non-standard (e.g.,customized), as desired or required. The connector can be configured tobe inserted into a stimulation device and/or controller in order toselectively energize the electrodes included in the lead assembly and/orotherwise electrically couple the electrodes to the stimulation deviceand/or controller (e.g., to provide electrical power to the lead, tosend and/or receive electrical signals to and/or from electrodes, etc.).As discussed in greater detail herein, in some arrangements, the leadincorporates a seamless or substantially seamless outer surface (e.g.,from the perspective of the outer shape of the lead) from the proximalend to the distal end. In some embodiments, the proximal end or aspectof the lead is configured to be inserted directly into a stimulationdevice or other component to selectively energize one or more electrodesand/or otherwise electrically couple the electrodes to the stimulationdevice or other component. By way of example, in some arrangements, theouter diameter of the lead from the proximal end to the distal endchanges a maximum of 0% to 5% (e.g., 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0to 1, 0 to 0.5%, values between the foregoing values and ranges, etc.).In other embodiments, the outer diameter of the lead from the proximalend to the distal end changes a maximum of 5% to 10%. Standard medicalconnectors, e.g., as outlined herein, are typically at least 2 timeslarger than the outer diameter of the described lead assembly. While thegreater size of said connectors is advantageous for handling andconnecting to peripherals, it limits the usability of traditionalinsertion tools. In contrast to having a larger connector on theproximal end, incorporating a smaller deviation in outer diameter alongthe length of the lead assembly advantageously permits a user towithdraw seamlessly insertion tools or other elements used to facilitateentry towards the anatomical target of interest. However, if largeconnectors are desirable, insertion tools of other elements may need tobe designed to be separable or peelable to facilitate removal of saidtools.

In other arrangements, the lead incorporates a seamless or substantiallyseamless (e.g., from the perspective of the outer shape of the lead)from the proximal end to just proximal to the distal end. For example,as illustrated in FIG. 40A, the distal end of the lead assemblycomprises a conductive element 1108 that has a rounded shape (e.g.,along the distal end). Thus, in such configurations, the outer diameteror other cross-sectional shape of the lead assembly is constant orsubstantially constant from the proximal end to or near the distal end.As discussed above, according to some embodiments, the outer diameter ofthe lead from the proximal end to the distal end changes a maximum of 0%to 5% or 5% to 10%.

In other arrangements, shown in FIG. 44A, the connector may comprise oneor more concentric rings 1126 that are conductive. Said rings can beconfigured to fully or partially encompass or otherwise surround thecircumference of the lead. In some embodiments, ring contacts are moreadvantageous compared to standard medical connectors. The advantages ofusing such contacts can be highlighted when employing an insertion tool(e.g., over the needle catheter) to place the electrode lead within thesubject percutaneously. Ring contacts can permit direct removal of theinsertion tool by sliding the lumen of the insertion tool 1128 over thelength of the lead body and removing it over the proximal aspect of thelead 1104, as shown in FIG. 44B. In the case of a standard medicalconnector, the tool may not be removed (e.g., may need to remain withthe lead assembly). In such an embodiment, the use of a peelable (orotherwise separable) catheter can overcome this obstacle, thereby addingto overall complexity, expense, etc.

In some embodiments (including any of the embodiments disclosed hereinor variations thereof), the lead comprises a stiffened proximal section(e.g., at least relative to distal sections or portions) that may beused to aid with insertion of the connector end of the lead into amating connector, port or other receptacle. The stiffened section canfacilitate a practitioner with handling the lead and/or inserting itinto a mating connector, port or receptacle in an enclosure or housingof a device that prevents the lead from falling out or otherwisedisengaging such lead assembly from such a separate device. In somearrangements, without the increased stiffness of the proximal portion,the lead may bend, kink and/or otherwise be damaged or undermined whileaiming to insert the lead into a mating connector. For example, theresulting deformities can increase the likelihood that the leadfractures, breaks, gets stuck, etc. or that the conductive wires withinthe lead break or fracture resulting in a failed lead. The addition of astiffened section or portion along the proximal end of the lead assemblycan be helpful from a durability, strength and the other physicalproperties, especially in light of the relatively small outer diameteror other cross-sectional dimension of the lead (e.g., circular lead).For instance, in some embodiments, the diameter or other cross-sectionaldimension of the lead is 0.1 to 5 mm (e.g., 0.1-0.2, 0.2-0.3, 0.3-0.4,0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4, 4-5,1-4, 0.5-4, 1-4, 0.1-5, 4-5, 3-5, 2-5 mm, ranges between the foregoing,etc.).

In some embodiments, the length of the stiffened proximal section is 0.5to 5 cm (e.g., 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-2, 2-3, 3-4,4-5, 1-4, 0.5-4, 1-4, 0.1-5, 4-5, 3-5, 2-5 cm, ranges between theforegoing, etc.). In some arrangements, the length of the stiffenedproximal section is at least as long as the distal aspect. In otherarrangements, the length of the stiffened proximal section is 10-100%the length of the distal aspect.

In some embodiments, the stiffened proximal section may comprise one ormore inserts that helps improve the assembly's resistance to fracturingand/or other damage. In some arrangements, such an insert or othermember comprises a relatively high tensile modulus. In somearrangements, such materials include plastics, metals, alloys and/or thelike with tensile moduli greater than 10 GPa. In some arrangements, suchinserts or other members have a melting temperature greater than themelting temperature of the outer jacket. In some embodiments, this canbe helpful as assembly of the lead may require the jacket to reflow(e.g., melt or shrink) over the insert. For example, the distal sectionmay comprise a polymer jacket with a melting temperature of 130 to 160°C. and with overall Young's modulus between 0.01 to 0.05 GPa; theproximal section may comprise of a polymer jacket with a meltingtemperature of 160 to 175° C. and with overall Young's modulus of 100 to250 GPa which includes the stiffening insert.

In some embodiments, the lead comprises of two sections, a relativelyrigid proximal section and a less rigid and shapeable distal section.The rigid proximal section may be inserted directly into a peripheral orstimulation device while the distal shapeable section may bepercutaneously inserted through tissue to interface a target nerve. Forexample, the distal section may comprise a polymer jacket with a meltingtemperature of 130 to 160° C. and with overall Young's modulus of 0.01to 0.05 GPa; the proximal section may comprise of a polymer jacket witha melting temperature of 160 to 175° C. and with overall Young's modulusof 100 to 250 GPa which includes the stiffening insert.

In some embodiments, the lead comprises three or more (e.g., 3, 4, 5,more than 5) distinct sections with each successive section havingratios of tensile moduli greater than the previous section. For example,in some embodiments, in a lead with three sections: a distal aspect, abody aspect and a proximal aspect, the ratio of tensile moduli isgreater in the body than the distal aspect, and greater in the proximalaspect to the body or distal aspect. More specifically, in someconfigurations, the body aspect has a tensile modulus ratio of 1.5 to 5times (e.g., 1.5 to 5, 1.5 to 4, 1.5 to 3, 1.5 to 2, 2 to 5, 2 to 4, 2to 3, 3 to 5, 3 to 4, ratios between the foregoing, etc.) the distalaspect. In some embodiments, the proximal aspect has a tensile modulusratio of 10 to 1000-20000 times (e.g., 10 to 1000, 10 to 100, 100 to500, 500 to 1000, 250 to 750, 300 to 700, 10 to 200, 10 to 500, 100 to20000, 10000 to 20000, 10000 to 30000, 20000 to 30000, 20000 to 25000,20000 to 40000, 30000 to 50000, etc.) greater than the body or distalaspect.

In some embodiments, the insert or other member spans the entire lengthof the proximal aspect and a part of the body aspect. In otherembodiments, the insert or other member spans only partially the lengthof the proximal aspect (e.g., 10 to 90, 20 to 70, 30 to 60, 40 to 50%,percentages between the foregoing, etc.). In some arrangements, theinsert may span only the length or a portion of the proximal aspect butnot any part of the body or distal aspect.

In some embodiments, each of the distinct sections may comprise of ajacket color different from one or more other sections of the lead todistinguish the sections from one another. In some examples, the colorof the proximal jacket may match the color of the mating connector orhousing or enclosure where the lead is to be inserted.

In some embodiments, as shown in FIG. 44C, the space between proximalconcentric ring contacts that do not span the full circumference of thecylindrical lead may contain a groove or other recess or feature 1130.Such groove 1130 may be used as a key to insert the lead into a stimulusgenerator unit.

In some embodiments, the electrode lead body 1100 with multipleconductive elements 1108 (e.g., as described herein) may beadvantageously used to measure action potentials. In one example, amulti-element electrode lead is placed near an injured nerve. In somearrangements, the electrode can be shaped to track the anatomical courseof the nerve. Proximal conductive elements can be configured to measurean evoked response in the injured nerve in response to stimulus derivedfrom distal conductive elements. In some arrangements, such an“upstream” measurement is used (either alone or together with some othermeasurement or metric) to confirm a validation condition. In somearrangements, the recording electrode configuration comprises amonopolar, bipolar, tripolar, or other configuration, as desired orrequired by a particular design or application. In some embodiments, thedistal conductive tip is configured to create a monopolar electric fieldin conjunction with a distal reference electrode. In some arrangements,the distal reference electrode is a surface patch electrode (or someother type of surface electrode) with integrated electronics. In yetanother embodiment, the distal conductive tip with other conductiveelements 1108 is configured to create a bipolar electric field. In someembodiments, more than 2 conductive elements (e.g., 3, 4, 5, more than5, etc.) are used to steer or otherwise direct current more precisely totarget an injured nerve, specific fascicles within an injured nerveand/or another targeted anatomical structure. Said element may bearranged in as circumferential elements (e.g., ring electrodes),segmented elements (e.g., partial ring electrodes), or other shapes. Insome embodiments, a plurality of conductive elements is used to deliverelectrical stimulus to a target nerve and/or measure bioelectricalsignals from the target at various positions along the length of thetarget nerve.

In some embodiments, as shown in FIG. 45, the distal end of theelectrode lead may include an indicator. Such an indicator can bepositioned along any other portion of the lead, either in addition to orin lieu of the distal end. In some arrangements, the indicator cancomprise a LED 1136. In one example, the LED may be used to indicate avalidation condition (e.g., successful action potential capture withproximal electrode conductive elements). It may be advantageous toincorporate an indicator within the surgical field as a surgeon's visualattention is directed to the site of nerve repair or electrode interfacearea, whereas the stimulus generator may be placed immediately outsidethis field of view. Without diverting a surgeon's attention, the surgeonmay manipulate (e.g., move and/or shape) the lead and be informed by theindicator that a validation condition has been confirmed.

While neuroregenerative therapy has not been shown to be a chronictherapy, it may be advantageous to maintain an electrode near an injurednerve to deliver therapy other than neuroregenerative therapy. Suchtherapies may include, for example, pain management therapy whichtraditionally has been a chronic therapy. Percutaneous electricalstimulation can be employed to deliver pain management therapy.Typically, such chronic stimulation paradigms require more sufficientanchoring of a nerve interface. In the case of the embodiments disclosedin the present application, the shapeable aspect(s) (e.g., distalaspect) may be utilized to surround, at least partially, a nerve forlong-term nerve interfacing as in the context of pain managementtherapy.

Long-Term Implantation

In some embodiments, the ability to apply a bioadhesive for long term orchronic implantation may be advantageous. Long term or chronicimplantation may be defined as greater than 30 days, for which,typically beyond this time frame, a chronic inflammatory and foreignbody response occurs and as defined by ISO 10993-1. The adhesivematerial may act as an interface to secure or anchor the electrode leadbody and/or conductive elements to the nerve, while maintaining a shapedconformation to the surrounding anatomical tissue via the electrodelead's ability to be shaped as previously described herein.

In some embodiments, the tissue adhesive comprises a biomaterial withsome, any, or all of the following properties: at least partiallybiodegradable, at least partially bioerodible, at least partiallybioresorbable, at least partially biocompatible, at least partiallybioinert and/or the like. The biomaterial can include a single materialor can include two or more materials, such as, for example and withoutlimitation, a polymer, an elastomer, a composite material, particles,molecules, layered materials, gels and/or the like. In some embodiments,the polymers are synthetic, natural, hybrids, chemically-modifiedversions of any of these and/or the like, as desired or required.Synthetic polymers can include, but are not limited to, polyethyleneglycol (PEG), poly(N-isopropylacrylamide) (poly(NIPAAm)),poly(lactic-co-glycolic acid) (PLGA), polyurethane (PU) and/or the like.Natural polymers include, but are not limited to, fibrin, collagen,gelatin, derivatives thereof and/or the like. Chemical modifications topolymers may include, but are not limited to, attachment, inclusion, orpresence of bioadhesive functional groups, such as catecholamines. Forexample, a bioinspired bioadhesive component isL-3,4-dihydroxyphenylalanine (DOPA), which achieves its superioradhesive properties mainly due to the presence of a catechol functionalgroup.

In some embodiments, the bioadhesive may be tunable or otherwisemodifiable and may be present in the body and function as an adhesivefor a controlled or pre-defined time period. Tuning of the bioadhesiveto achieve desired characteristics or responses may be a function of thechemical, material, and/or physical properties, or as a function of anexternally-applied stimulus. Tunability or modifiability of abioadhesive as used herein refers to the design and/or control of anyone or more of the aforementioned factors to achieve desiredcharacteristics or responses, such as, for example, and withoutlimitation: the biodegradation rate, the release profile of bioactivemolecules or agents, the adhesion strength, the mechanical properties(e.g., shear, compressive, and/or tensile moduli), or the responsivenessto external stimuli.

In some embodiments, the bioadhesive may degrade within an acute orrelatively short time period (e.g., less than 30 minutes, 30 minutes to1 hour, 1 to 6 hours, 6 to 12 hours, 12 to 24 hours, 1 to 30 days,values between the foregoing values or ranges, etc.). Such an acute timeperiod as used herein is based on what is typically acceptable for acutehuman implants as defined by ISO 10993-1.

According to some arrangements, degradation of the bioadhesive within anacute time period may be advantageous for application ofneuroregenerative therapy since, for example, the bioadhesive wouldsecure the lead to the nerve at the beginning of the treatment. This canhelp prevent mobility of the lead assembly and ensure optimal or moreadvantageous contact during stimulation. Further, degradation of thebioadhesive during the treatment can allow for easy removal of the leadpost-therapy with little or no resistance from the bioadhesive.

In some embodiments, the bioadhesive may be tuned or otherwiseconfigured to degrade over a longer time period (e.g., 30 to 40 days, 40to 50 days, 50 to 60 days, 60 to 70 days, 70 to 80 days, 80 to 90 days,90 to 100 days, 100 to 120 days, greater than 120 days, time periodsbetween the foregoing ranges, etc.). This may be advantageous inscenarios that require long term implantation of the lead forneuroregenerative therapy and/or pain management purposes. In suchscenarios, it may be advantageous or desired to design the implantedmaterials so as to modulate this host response. Such designconsiderations may include, but are not limited to, biocompatibility,bioresorbability, use of bioinert materials, delivery ofanti-inflammatory or immunosuppressive agents and/or the like.

Anchoring Using Glues or Other Adhesives

In some embodiments, the bioadhesive is in the form of a bulk gel orother gel or gel-like material (e.g., hydrogel, glue, other adhesive,other polymeric material, etc.). The gel can be pre-formed (e.g., priorto implantation), can be configured to be formed in situ, or acombination of both. In some arrangements, a pre-formed gel may beapplied directly to the anatomical site of interest and/or surface ofthe electrode lead prior to or during lead implantation (e.g., toachieve adhesion between the lead and tissue surfaces). In someembodiments, pre-formed bulk gels require no mixing prior toapplication. Such arrangements can function (e.g., immediately,promptly, etc.) as an adhesive upon contact to the surfaces of interest.Such pre-formed bulk gels may include, but are not limited to,pre-existing commercial materials (e.g., Dermabond™, Indermil®,Liquidband®, etc.), custom-made materials, or a hybrid of these.

In some embodiments, the bioadhesive is formed and/or mixed at the timeof application. As used herein, in situ formation refers to chemicaland/or physical reactions that occur to result in the formation of thefinal bioadhesive. The chemical or physical mechanisms by which thisoccurs can include, but are not limited to, interfacial bonding,covalent or ionic bonding, crosslinking (e.g., chemical, physical,enzymatic, photochemical), photopolymerization, thermal curing (e.g.,thermosetting), oxidation and/or the like. In some embodiments, suchreactions may be initiated by physical mixing of multiple componentsand/or application of an external stimulus. Additional initiationmechanisms can be used, either in lieu of or in addition to thoseindicated in the preceding sentence. In some embodiments, in situ formedbioadhesives may be pre-existing commercial tissue glues or adhesives(e.g., fibrin-based gels like Tisseel™, PEG-based gels like Coseal™,etc.), custom-made materials, or a hybrid of these.

In other embodiments, the bioadhesive comprises (e.g., is in the formof) a coating or film on the surface of the electrode lead. Thecoating/film can incorporate or otherwise include physicalcharacteristics (e.g., rough surface topography, micropatterning, etc.)to facilitate adhesion of the bioadhesive (e.g., as the primarymechanism, as a supplemental mechanism, etc.). In some embodiments, theadhesive functionality of the coating/film may be activated prior to,during and/or after device implantation. In some embodiments, thebioadhesive is already functional. In some embodiments, activationrequires removal of a protective layer that prevents adhesion prior toapplication. In some embodiments, the coating/film is adhesive due touniquely-designed chemical and/or physical properties. Such propertiesmay include, but are not limited to, topographical patterns or indents,surface charge (anionic, cationic, etc.), etc. In some embodiments, thebioadhesive coating can become functional or active (e.g., immediately,after the passage of a certain time period, etc.) upon contact to thesurfaces of interest by the adhesive. In other arrangements, theadhesive functionality is activated by application of an externalstimulus. Stimuli can include, but are not limited to, one or more ofthe following: electricity or other electrical stimulus, thermal energy,light energy, chemical, pressure, acoustic energy, other types ofenergy, etc.

In some embodiments, anchoring of the electrode lead body 1100 mayemploy or use a form of bioadhesive or other adhesive tape 1300. In somearrangements, the tape is included with the electrode lead assembly. Inarrangements such as this, it may be advantageous to use a separatedevice and/or actuator to release or deploy the bioadhesive tape anchor.The bioadhesive tape can include one or more wings/flaps that areattached to the tip of the lead and configured to unfurl or otherwiserelease in response to a designated control. For example, once a leadassembly is positioned at a desired anatomical position (e.g., on oradjacent to a peripheral nerve, proximal to the injury and/or repairsite), a designated button or other controller on a control system maybe activated (e.g., pushed) to deploy or otherwise release thebioadhesive tape at the distal tip of the lead. In some embodiments,prior to deployment, the bioadhesive tape can be configured to be moved(e.g., furled inwards toward the lead and flush with the edges of thelead to prevent catching on any tissue during lead placement). Afterdeployment, the bioadhesive tape may release (e.g., unfurl) and conform(e.g., instantaneous, generally instantaneously) to and adhere the leadto the surrounding anatomy. In other arrangements, the tape is aseparate device that is applied prior to, during and/or after deviceimplantation.

In some arrangements, the tape 1300 is applied semi-circumferentially orcircumferentially, either partially or completely wrapping around acircular or cylindrical anatomical site, or interfacing the electrodelead to an anatomical site with adhesive functionality on both faces ofthe tape. In one example, the tape may be used to anchor an electrodelead body 1100 to a nerve structure 1110 by placing the tape 1300proximal to conductive elements 1108, as shown in FIG. 46A. In yetanother example, shown in FIG. 46B, the tape 1300 may be placed betweenconductive elements 1108.

In some arrangements, securing the lead to the anatomical site isachieved with one or more (two, three, etc.) bioadhesive tapes. In someembodiments, the tape is rectangular, circular, cylindrical, elliptical,or of any other geometry.

In some embodiments, the tape is relatively thin (e.g., 1 to 10 μm, 10to 50 μm, 50 to 100 μm, less than 1 mm, 1 to 9 mm, any values betweenthe foregoing ranges or values, etc.) or relatively thick (e.g., 9 to 10mm, 10 to 15 mm, greater than 15 mm, etc.).

In some embodiments the tape may have a controlled and tunablebiodegradation profile, such that it degrades within a desired timeframeto facilitate easy removal of the lead from an anatomical site.

In other embodiments, the lead anchor tape may be disabledinstantaneously by a control on the device. In embodiments such as this,the tape may stay attached to the lead during removal, but have materialor physical properties that permit smooth removal of the lead andbioadhesive through the para-incisional site. In other embodiments, thecontrol may induce ejection of the tape from the lead prior to leadremoval. In this case, the tape would remain at the anatomical siteduring and following lead removal, but it would be advantageous for itto be biocompatible and rapidly biodegradable (e.g., less than 1 hour, 1to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 12 hours, 12 to 24 hours, 1to 30 days, any value between the foregoing values or ranges, etc.) suchas to not induce a negative immune response as it degrades.

Adhesive Delivery and Curing Methods

In some embodiments, the bioadhesive includes a pre-mixed and pre-formedfluid solution that is delivered to a desired anatomical site viainjection and is configured to function as an adhesive instantaneously.One example may include the pre-formed bioadhesive being dispensed froma built-in or attached reservoir in the neuroregenerative stimulationsystem and flowed (or otherwise delivered) through a cannula or otheropening (e.g., lumen) that is built into or otherwise included withinthe corresponding lead. In other scenarios, such as those in which thepre-formed bioadhesive is a pre-existing commercial product, thebioadhesive solution can be applied to the desired anatomical site priorto and/or immediately after adhering or otherwise at least partiallysecuring at least a portion of the lead to and/or near the same site.

In other embodiments, the bioadhesive is formed and/or functionallyactivated in situ. In some arrangements, in situ formation occurs viaphysical and/or chemical crosslinking by mixing (e.g., at leastpartially in situ) two or more compatible polymer precursor solutions.In some arrangements, a multi-barrel syringe or extrusion device iseither built-in (or otherwise included with) or external to (orotherwise not include with) the stimulation system. Such a syringe orother delivery device can be configured to house (e.g., at leastpartially, completely, etc.) the precursors (or other materials to becombined) separately such that crosslinking does not occur prior to use.In some arrangements, mixing and crosslinking occurs proximal to thesite of application. In other arrangements, mixing and crosslinkingoccurs directly at the site of application. Two or more (e.g., 3, 4, 5,more than 5, etc.) materials can be configured to be mixed or combinedat least partially in situ.

In some arrangements, for any of the embodiments disclosed herein, alead assembly includes a single lumen or other opening to facilitateflow of materials and/or other substances (e.g., a single fluid or othersolution, two or more fluids or solutions, etc.) to or near the distaltip and delivery site. In other arrangements, multiple lumens, cannulasand/or other openings are included in the lead assembly to permitdelivery of separate solutions, fluids and/or other materials to or nearthe distal tip and to or near a targeted delivery site.

In some embodiments, the materials or other substances (e.g.,precursors) are mixed to form crosslinks, and the mixed material isextruded and applied directly to or near the desired site, using aseparate device or devices. The mixed material may be in its completelycrosslinked form or partially crosslinked at the point of extrusion. Insome embodiments, complete crosslinking may be desired to achieve fastgelation or otherwise activate the bioadhesive quickly. In otherembodiments, it may be advantageous to extrude a partially crosslinkedmaterial to allow for slower gelation time and active the bioadhesive ata slower rate.

In some embodiments, bioadhesive solutions are applied to a cuff-likedevice that may act as a localized chamber mechanism to at leastpartially contain the bioadhesive along, adjacent and/or near the nerve.Said cuff-like devices may be configured to act as a mold that permitsonly a thin layer of bioadhesive to be extruded onto a nerve orenveloped structure. Such an application is advantageous as bulkhydrogel delivery may compress a nerve and cause nerve injury. Such anapplication can also be advantageous as the use of a cuff-like devicemay help isolate (e.g., fully, partially, etc.) adhesive from thesurrounding tissue.

In some arrangements, it may be advantageous to extrude pre-loadedprecursor solutions from a double-barrel syringe or other deliverydevice having a mixing tip directly onto an anatomical site, thenadhered the lead to that site. For example, Tisseel™, a commonly-usedcommercial surgical tissue adhesive that could be used to anchor thelead to a nerve during application of long-term neuroregenerativetherapy, as Tisseel™ remains active as an adhesive and biodegradeswithin 14 days. It is composed of fibrinogen and thrombin precursorsolutions that crosslink to form fibrin (the bioadhesive) when mixed. Itis packaged in a double-barrel syringe system that houses the twoprecursors separately. Upon extrusion of the syringe, the precursorsenter the mixing chamber at the tip of the syringe, whereby, uponcontact, the precursors undergo a chemical reaction to form crosslinks,resulting in the formation of fibrin, the bioadhesive. In somescenarios, Tisseel™ may be extruded through a cannula in the body of thelead using an adaptor. In other scenarios, Tisseel™ may be applied to asurface on the lead tip and/or anatomical site prior to lead positioningand to anchor the lead to the nerve for treatment.

In an embodiment, the bioadhesive is photocurable and configured to beactivated (e.g., photo-activated) by applying light (e.g., of a specificwavelength and/or other property). The inactivated bioadhesive may beapplied to a site of interest (e.g., on tissue, the electrode leadsurface, combination thereof, etc.). In some embodiments, once the leadassembly is positioned in a desired location, light can be applied(e.g., for a desired or required time period) to cure and activate thebioadhesive, and thereby ensure sufficient, at least partial, anchoringof the electrode lead in a desired place. In some embodiments, thebioadhesive is also photodegradable and degradation of the material iscontrolled by application of light of a wavelength (e.g., a differentwavelength than that required to cure the adhesive).

In some scenarios, it may be advantageous for the bioadhesive to containboth photocurable and photodegradable moieties that cure or degradeinstantaneously in response to application of a unique wavelength. Forexample, the bioadhesive may comprise an ortho-nitrobenzyl protectingfunctional group that is reactive to light in the visible spectrum(wavelengths between 400 to 700 nm) and cured within seconds of lightexposure. This could be applied to adhere (e.g., instantaneously,rapidly, within a particular time duration, etc.) an electrode lead to aproximal nerve segment prior to electrical stimulation therapy. Thebioadhesive could also include a diortho-nitrobenzaldehyde moiety thatis reactive to UV light (10 to 400 nm) and configured to degrade (e.g.,instantaneously, rapidly, within a particular time duration, etc.) uponexposure to detach the lead from the nerve and allow for easy removal ofthe lead following treatment.

According to some embodiments, as shown in FIG. 47, a bioadhesivedispensing device 1310 and light source 1312 are individual devices,e.g., separate from the stimulation system and may be included as partof a kit. The bioadhesive dispensing device can comprise a reservoir,opening, other chamber and/or the like 1314 with a pre-loaded amount ofbioadhesive that is extruded through a nozzle 1316 at a controlled flowrate (e.g., syringe dispenser) or using a plunger 1317. The light sourcemay comprise a power supply, light source, transmission mechanisms(e.g., bulbs, optical fiber cables, etc.), controls 1318 to turn on/offor change the light type (e.g., buttons or switches) and/or any othercomponents or features, as desired or required.

In some embodiments, the light source is included in a handheld deviceor wand 1312, in which the tip and/or other portion is configured toemit light. In some arrangements, it may be advantageous to transmitlight through the device tip to concentrate the photoenergy to onelocation, for localized small-area illumination of the bioadhesive.

In other scenarios, it may be advantageous for at least part of thedevice (e.g., a portion of the device, the entire device, etc.) to beconfigured to transmit light as it is held horizontally (or in someother orientation relative to a reference point or plane), especially incases where a larger surface area of bioadhesive needs to be illuminatedat one time.

In another embodiment, the photoresponsive bioadhesive applicator andlight source make up (or are included in) one device, separate from thestimulation system. In one arrangement, the device is a handheld toolthat comprises a bioadhesive reservoir, a power supply, a light sourceand transmission mechanisms, and is configured to control or otherwiseregulate at least one aspect of the dispensing of bioadhesive (e.g.,automated button dispenser, manual plunger, etc.) and is configured tocontrol or otherwise regulate light transmission.

According to some arrangements, as depicted in FIG. 48A, the bioadhesivedispensing nozzle tip 1320 contains one or more light sources 1322(e.g., LEDs). Such light sources 1322 can be configured to be controlledby one or more controllers (e.g., buttons, switches, dials, etc.) on thebody of the device and can be configured to transmit or otherwiseprovide light of a desired type (e.g., UV or visible light).

In some arrangements, as shown in FIG. 48B, it may be advantageous forat least part of the device shaft to transmit or otherwise provide lightas it is held in a particular orientation (e.g., horizontally). In someembodiments, such a configuration can be desirable in instances where alarger surface area of bioadhesive must be illuminated at one time. Thebioadhesive dispensing control may allow the user to dispense an amount(e.g., preset amount, customizable amount, etc.) of the adhesive (e.g.,up to the maximum reservoir limit).

In some embodiments, as shown in FIG. 48C, the dispenser may beconfigured to dispense a curable bioadhesive 1330 that may be used toanchor an electrode lead body 1100 or distal aspect of an electrode 1102to a nerve structure 1110. The dispenser can be configured to also curesuch a bioadhesive. The device can include an indicator (e.g., a visualindicator, another type of indicator, etc.), such as, for example, butnot limited to, sensor output to a display (e.g., LCD screen, otherdisplay, other output, etc.). Such a display can be configured todisplay various information, including but not limited to the selectedor preset volume of bioadhesive to be dispensed, the volume ofbioadhesive remaining in the reservoir and/or the like, as desired orrequired. The visual indicator can also be configured to provideadditional information, such as, for example, information regarding thelight source (e.g., if the light source is on or off), regarding thewavelength of light being transmitted or to be transmitted, regardingthe time of illumination (e.g., elapsed, remaining time, etc.) and/orthe like. In some embodiments, the bioadhesive itself is configured tochange color (e.g., in real-time, after another condition is satisfied,etc.) to indicate appropriate curing.

In some embodiments, bioadhesive solutions are applied to a cuff-likedevice that may act as a localized chamber mechanism to contain thebioadhesive strategically near or along the nerve (or another locationrelative to the nerve). Said cuff-like devices may be configured to actas a mold that permits only a thin layer, a patterned layer, ormultipatterned layer of bioadhesive to be extruded onto a nerve orenveloped structure. Said device may also comprise a light source and/orlight diffusing elements directed internally at the enveloped structureand may be utilized for curing a polymer.

In some arrangements, it may be advantageous to pre-program thephotoresponsive bioadhesive applicator and light source system. Forexample, the system may be operated in the following manner with one ormore preset controls (e.g., built-in or incorporated controls) to securea lead tip to a nerve: (1) operate a button or other controllerconfigured to be pressed or otherwise controllable to apply a volume ofbioadhesive (e.g., a controlled volume, at a constant flow rate,directly, indirectly, uniformly, non-uniformly, etc.) on or near thesurface of a nerve, (2) position or otherwise locate a lead on thesurface of the nerve, where the bioadhesive is an interface between thetwo surfaces, and (3) press or otherwise activate another button orother controller to activate one or more light sources (e.g., for apreset, predetermined or fixed time duration (e.g., e.g., 30 seconds, 1minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 5 to 10 minutes,values between the foregoing ranges, greater than 10 minutes, etc.)).Such a time period can be selected based on, at least in part, therequired time for photocuration and activation of the bioadhesive. Insome embodiments, the bioadhesive passively biodegrades over acontrolled period of time to allow for easy lead detachment and removalat the end of the biodegradation period. In other embodiments, thebioadhesive degrades instantaneously or rapidly upon application oflight of a wavelength different than the requirement for curing.

In some embodiments, the bioadhesive application system and light sourceare built or otherwise incorporated into the stimulation system and/orlead. In one arrangement, the bioadhesive solution reservoir may behoused in the stimulation unit. In other arrangements, the reservoir maybe an external component (e.g., not incorporated into or a part of thestimulation and/or lead assembly), as desired or required. In onearrangement, the bioadhesive is a solution that is extruded or otherwisepositioned through (e.g., at least partially) the body of the leadassembly in one or more contained channels, reservoirs and/or otherportions. In some embodiments, the bioadhesive is configured to exit ator near the tip or distal end of the lead assembly.

In one example, as illustrated in FIG. 49A, the bioadhesive solution isconfigured to exit near or at a distal portion of the electrode leadbody 1102 (e.g., through one or more dedicated perfusion ports, holes,pores, apertures and/or other openings 1340). Such openings can belocated at or near the distal end of the electrode lead body betweenconductive elements 1108. In some embodiments, the bioadhesive may alsoexit through one or more ports, holes, pores, apertures and/or otheropenings that may be located along the distal aspect or portion,proximal aspect or portion, location between the proximal and distalportions, combinations thereof, etc. of the electrode lead body orassembly.

According to some arrangements, as shown in FIG. 49B, it may beadvantageous for the bioadhesive to be configured to exit throughnumerous (e.g., two or more) apertures 1340 located along or near thedistal and/or proximal lead body to achieve uniform extrusion around thecircumferential surface area of the lead tip for optimal adherence to ananatomical site. A lead assembly can include any arrangement of openings1340 to permit the bioadhesive to be delivered to specific areas of thelead assembly and/or the anatomy of the subject.

In another arrangement, the bioadhesive comprises a coating or filmlocated on the surface of the lead assembly. In some embodiments, such acoating or film extends from the tip to a preset length (e.g., theentire length of the lead, up to half the length of the lead, the distalquarter length of the lead, any other portion of the lead, etc.), andcan be activated/deactivated by application of light (e.g., light ofunique wavelengths) and/or any activation source.

In some arrangements, the light source is located, at least in part, atand/or near the tip of the lead assembly and may be controlled by one ormore controls (e.g., buttons or other controls located on a stimulationunit, another device, etc.).

According to some embodiments, the activating light source includes oneor more sets of light generators (e.g., one or more LEDs, one or moreother light sources, etc.). In other arrangements, the light source isencased (e.g., partially or completely) within a housing of thestimulation unit and/or transmitted through the body of the leadassembly (e.g., through mechanisms like, for example, optical fibers,other transmitters, etc.). In some arrangements, at least a portion ofthe lead assembly is at least partially translucent or transparent topermit the transmission of light through a dedicated portion of the leadbody or in its entirety.

In some embodiments, the activation and/or deactivation of thebioadhesive is controlled by other external stimuli, which may include,for example, but are not limited to, thermal energy, electrical energy,photoacoustic energy, chemical and/or biochemical stimuli. In someembodiments, the bioadhesive is thermoresponsive or thermosensitive. Insuch an arrangement, the bioadhesive may be inactive at temperatureranges above/below normal physiological temperature (e.g., ambienthospital storage temperature), but configured to become active onceexposed to temperatures within the normal physiological range.

In other embodiments, the bioadhesive is responsive to electrical energystimuli. In some scenarios, the bioadhesive may be activated ordeactivated in response to electrical stimulus of given parameters orwithin a specified range of parameters. These parameters may include,but are not limited to, differences in stimulation current, voltage,amplitude, pulse frequency, alternating or direct current and/or thelike. In some arrangements, activation of the bioadhesive can beconfigured to occur in response to electrical stimulus parameters thatare the same (or substantially the same) or different than that ofneuroregenerative therapy. For example, after an electrode lead assemblyhas been positioned on or near an anatomical site with the bioadhesiveas an interface between the two surfaces. Controls on the stimulationunit can be used to apply a desired dose (e.g., predetermined, fixed orvariable, etc.) of electrical stimulation, such that the bioadhesive iscured and activated to attach the lead to the anatomy.

In some embodiments, the electrical stimulation dose that is deliveredwith respect to the bioadhesive is the same or generally the same as thedose for neuroregenerative therapy. In some embodiments, such astimulation dose is activated upon start of the treatment. In otherembodiments, the curing dose may be different than that ofneuroregenerative therapy, such as, for example, stimulation at the samecurrent output, but lower pulse frequency (e.g., less than 1 Hz, 1 Hz, 1to 2 Hz, 2 to 3 Hz, 3 to 4 Hz, 4 to 5 Hz, 1 to 5 Hz, 5 Hz, 10 Hz, 15 Hz,25 Hz, 5 to 10 Hz, 10 to 15 Hz, 15 to 20 Hz, 20 to 25 Hz, frequencieswithin the foregoing ranges and/or between the foregoing values, greaterthan 25 Hz, etc.). Such a frequency can be equal to, less than orgreater than the frequency used for neuroregenerative therapy).

According to some arrangements, the bioadhesive is activated uponelectrical stimulation. Such activation can occur instantaneously or atsome point following activation of electrical stimulation. In somearrangements, the various embodiments disclosed herein can have twostimulation phases: (1) the bioadhesive curing stimulation phase, and(2) the neuroregenerative therapy stimulation phase. In someembodiments, the curing dose of electrical stimulation is applied for arelatively short time, such as, for example, less than 5 minutes (e.g.,less than 30 seconds, 30 seconds, 1 minute, 2 minutes, 30 seconds to 1minute, 1 to 2 minutes, 2 to 3 minutes, 3 to 5 minutes, values betweenthe foregoing ranges or values, etc.) in order to activate thebioadhesive. In other arrangements, the curing dose is required to beapplied for longer lengths of time (e.g., 5 minutes, 10 minutes, 5 to 10minutes, greater than 10 minutes, values between the foregoing ranges orvalues, etc.). In some scenarios, it may be advantageous for thebioadhesive to be activated instantaneously or within a short timeperiod following electrical stimulation, such that the total surgicaloperating time is minimized or otherwise reduced.

In some arrangements, the bioadhesive is activated via electricalstimulation and deactivated through passive biodegradation to allow foreasy removal of the lead assembly (e.g., following a biodegradation timeperiod). It may be advantageous, under certain circumstances, to designthe biodegradation period such that it is within the time periodrequired for neuroregenerative therapy. Thus, the biodegradation periodcan be equal to or greater than the time period for neuroregenerativetherapy.

According to some arrangements, the bioadhesive is both activated anddeactivated via electrical stimulation. In such an arrangement,application of the electrical stimulus for deactivation of thebioadhesive may be the same or different than that required foractivation and/or neuroregenerative therapy. In one aspect, thebioadhesive may be activated with a specified curing dose of electricalstimulation, but deactivated when exposed to neuroregenerative therapyelectrical stimulation. In another aspect, the bioadhesive may beactivated with a specified curing dose of electrical stimulation, remainactive during neuroregenerative therapy, and then deactivated byapplying electrical stimulation of different parameters than the curingdose and neuroregenerative therapy.

In some arrangements, deactivation of the bioadhesive via electricalstimulation occurs instantaneously or over short or long time periods.For example, it may be advantageous to apply an electrical stimulus todeactivate the bioadhesive instantaneously following neuroregenerativetherapy in the acute setting to minimize the total lead removal time.

In some embodiments, the bioadhesive is responsive to photoacousticand/or other acoustic energy. For example, an ultrasound system may beused intraoperatively and/or or perioperatively in a multifunctionalmanner. In such arrangements, an ultrasound or other acoustic system canbe configured to (1) guide the user during lead placement, (2) allow theuser to visualize a lead assembly within, at least partially, in thesubject's anatomy, (3) activate the bioadhesive, (4) deactivate thebioadhesive and/or perform any other tasks. In some arrangements,activation/deactivation of the bioadhesive may require the same ordifferent photoacoustic energy parameters.

In some embodiments, the bioadhesive is responsive to chemical and/orbiochemical stimuli. In one aspect, the bioadhesive is pH responsive andactivated via exposure to physiological pH (pH 7.4). In some aspects,the bioadhesive is pH-responsive and activated/deactivated in responseto application of a solution with a pH above or below physiologicalconditions. For example, the bioadhesive may be positioned as aninterface between an anatomical site and an electrode lead, but onlyactivated when an acidic or basic solution (pH<7.4 or pH>7.4) is appliedto the area. The bioadhesive may also be deactivated via passivebiodegradation or in response to chemical changes, for example,application of a solution with a different pH than that of normalphysiological conditions.

In some embodiments, the bioadhesive is multifunctional and responsiveto chemical and/or biochemical stimuli (and/or other stimuli) to delivera therapeutic or non-therapeutic agent in addition to securing a lead toan anatomical site. For example, following securing of the lead to anerve, the bioadhesive may be configured to react when exposed tophysiological pH values and/or other physiological biochemical factors.In such circumstances, a neuroregenerative agent (e.g., nerve growthfactor, glial derived growth factor, Tacrolimus, etc.) can be releasedor delivered at a rate (e.g., a controlled rate) to synergisticallyboost the regeneration rate and enhance regeneration of an injuredperipheral nerve in combination with neuroregenerative electricalstimulation. Additionally, or alternatively, the bioadhesive may beconfigured to release or provide a pain modulation agent (e.g.,nonsteroidal anti-inflammatory drugs like aspirin and ibuprofen, otheragents, etc.) in combination with neuroregenerative electricalstimulation. Examples of pH-responsive bioadhesives include, but are notlimited to, oligo(methyl methacrylate)-grafted poly(acrylic acid),modified poly(ethylene glycol), modified poly(amino ester), includingderivatives thereof.

Combination Systems

In some embodiments, the bioadhesive is configured to be multifunctionaland is configured to deliver bioactive and/or therapeutic molecules(e.g., in addition to maintaining certain adhesive properties andcharacteristics). Bioactive and/or therapeutic molecules that may bedelivered by the bioadhesive include, but are not limited to,anti-inflammatory agents (e.g., ibuprofen, celecoxib, diclofenac, etc.),anesthetics (e.g., lidocaine), immunosuppressive agents (e.g.,Tacrolimus, cyclosporin A, rapamycin, etc.), antimicrobial agents (e.g.,ciprofloxacin), steroidal or hormonal agents (e.g., erthropoetin,melatonin, testosterone, estrogen, etc.), neurological agents (e.g.,lithium, gapapentin, etc.), proteins and neurotrophins (e.g., brainderived neurotrophic factor, glial derived neurotrophic factor, nervegrowth factor, etc.), cells (e.g., stem cells, Schwann cells,macrophages, etc.), vitamins (e.g., vitamin B12, etc.), deliveryvehicles (e.g., nano/microparticles, liposomes, micelles, precipitates,etc.) and/or the like.

In some arrangements, the bioadhesive is tuned to deliver the bioactiveand/or therapeutic molecule within an optimal or desired timeframe. Insome arrangements, such a timeframe depends on, at least in part, themolecule(s), site of delivery, clearance rate, etc. Delivery can occuraccording to regular or irregular frequency (e.g., a constant or anon-constant rate), according to the design of the biomaterial andproperties of the molecule or agent and/or one or more other factors orconsiderations, as desired or required.

In one example, the bioadhesive is used to at least partially anchor theelectrode lead to a nerve that was surgically repaired for up to orgreater than 60 days (e.g., more than 60, 70, 80, 90, 100, 110, 120,150, 200, 250, 300 days, day values in between the preceding values,more than 1 year, etc.). Under such circumstances, the bioadhesive canbe multifunctional and can be configured to release an immunosuppressant(e.g., Cyclosporin A or Tacrolimus) at a constant rate for the durationthe lead is anchored to prevent or reduce the likelihood of a majorinflammatory or host immune rejection response to the implanted lead,that might otherwise result in premature removal of the lead,ineffective treatment, and pain or other negative or potentiallyproblematic physiological effects for the patient or other subject.

In some arrangements, it may be advantageous to deliver an agent ormultiple agents that enact or otherwise create certain desired effects.In some embodiments, more than one desired effect is created. Forexample, Tacrolimus (e.g., also known as FK506) is a commerciallyavailable immunosuppression agent that has also been proven to enhanceperipheral nerve regeneration in acute and chronic animal nerve injurymodels. Therefore, under certain circumstances, since the biologicalneuroregenerative mechanism of Tacrolimus is different than that ofneuroregenerative electrical stimulation therapy, the delivery of bothTacrolimus and electrical stimulation may act synergistically tooptimize or otherwise improve peripheral nerve regeneration beyond whatis achievable with application of either individual methods on theirown. Therefore, it may be advantageous to design the electrode leadbioadhesive such that it is also a therapeutic delivery device thatdelivers one or more therapeutics (e.g., Tacrolimus) in a desired manner(e.g., in a controlled manner) to synergistically boost or otherwiseenhance the neuroregenerative capacity of an injured peripheral nerve.This can be in addition to application of electrical stimulationtreatment. Furthermore, with the Tacrolimus example in mind, sinceTacrolimus is an immunosuppressant, delivery of this drug may alsoassist with mitigating the chronic immune or foreign body response toany of the implanted components.

In other aspects, the combination of neuroregenerative electricalstimulation and delivery of pro-regenerative agents may be desired(e.g., to create an optimal or enhanced effect) under certaincircumstances (e.g., for severe nerve injury models (e.g., chronicaxotomy, nerve plexus injuries, gap nerve injuries, etc.)). Currenttreatment strategies for gap nerve injuries requiring surgicalimplementation of nerve grafts (e.g., autograft, xenograft, allograft,etc.) or nerve conduits, remain largely insufficient for meaningfulregeneration and functional recovery post-injury.

Furthermore, some nerve graft types that are often selected due to theiravailability and lack of requirement for a secondary surgical site havealso been reported to induce acute and/or chronic host inflammatory orimmunogenic responses. In such cases, it may be advantageous orotherwise desirable to apply a multifactorial treatment strategy, inwhich surgical nerve gap repair using a graft or conduit,neuroregenerative electrical stimulation, local delivery ofanti-inflammatory and/or immunosuppresive agents and/or othermaterials/treatments are applied to enhance regeneration and prevent orreduce the likelihood of graft-rejection following nerve gap injury.

In some arrangements, following surgical repair of a nerve gap, theneuroregenerative stimulation system may be implemented. The lead may beinserted using a para-incisional approach and anchored into place with amultifunctional bioadhesive (e.g., according to any of the technologiesand methods described herein). In some aspects, the bioadhesive maycontain an immunosuppressant, such as, for example, Tacrolimus (FK506)or other immunosuppressive agents (e.g., cyclosporin A, rapamycin,etc.).

According to some embodiments, the bioadhesive may secure, at leastpartially, the lead to and/or near a site on the nerve (e.g., proximalto the repair site) and may also cover (e.g., completely, partially,etc.) the surface area of the corresponding nerve graft. The bioadhesivemay function to anchor or otherwise secure the stimulation lead for theduration and course of neuroregenerative electrical stimulation therapy.In some embodiments, it can be configured to remain for the therapy andto remain at the site for longer (e.g., 2 hours, 4 hours, 1 to 4 hours,less than 1 hour, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 4 to 16hours, 12 to 18 hours, 12 to 24 hours, 18 to 24 hours, 1 to 30 days, 30to 60 days, 60 to 90 days, time values within the foregoing ranges,greater than 90 days, etc.), as desired or required for a particularapplication or use.

Regardless of the exact time frame, for the corresponding duration, thebioadhesive can be configured to biodegrade and to deliver a therapeutic(e.g., Tacrolimus (FK506)) at a desired (e.g., controlled) rate. In someembodiments, such an embodiment can be configured to provide localimmunosuppression during the course of axon regeneration and graftremodeling. As previously discussed, in addition to being animmunosuppressant, Tacrolimus (FK506), for example, can be aneurotrophic agent. Therefore, under certain circumstances, controlledand local delivery of a substance (e.g., Tacrolimus) in combination withneuroregenerative electrical stimulation therapy may not only preventhost rejection of any nerve grafts and/or conduits, but may alsosynergistically encourage axonal regrowth and enhance nerve regenerationin a gap nerve injury model (and/or create some other beneficial effector result), beyond what is achievable with surgical treatments alone.

In another example, the bioadhesive is multifunctional and is also adrug delivery system for acute and/or chronic pain modulation purposes.In some aspects, the bioadhesive may act as a local delivery vehicle forpain-suppressing or pain-inhibiting agents (e.g., anti-inflammatoryagents, steroidal agents, local anesthetics, etc.). This drug deliverysystem may act synergistically or separately from pain modulationelectrical stimulation. The bioadhesive drug delivery system may betuned to release the drug payload depending on the optimal therapeuticwindow. In some aspects, it may be advantageous for the bioadhesive drugdelivery system to rapidly dispense the agent, whilst retaining itsadhesive and shapeability properties over the course of which the leadis to be implanted.

In some embodiments, it may be advantageous for the bioadhesive drugdelivery system to dispense the agent over a slower time course.

In some embodiments, the drug release profile may be continuous,non-continuous or occur at designed intervals (e.g., pulsed drugdelivery). For example, a peripheral nerve injury patient may receive anelectrical stimulation phase for neuroregenerative therapy and a secondelectrical stimulation phase for pain management therapy. A bioadhesivemay be used to interface and secure the electrode lead proximal to thenerve injury site during the neuroregenerative therapy phase andthroughout the course of pain modulation therapy phase. Furthermore, thebioadhesive may be designed to release a local dose of ananti-inflammatory and pain modulation agents, such as, but not limitedto, ibuprofen, pregabalin, gabapentin, topiramate, carbamazepine, etc.The release profile of the pain modulation agent from the drug deliverysystem may be linear, in which a constant dose and rate of the painmodulation agent is released over time to provide pain relief for thepatient over the course of their recovery, in addition to the painmodulation therapy phase delivered by electrical stimulation. Thebioadhesive may passively degrade over either or both of theneuroregenerative or pain modulation therapy time frames, such that whenit is time the remove the lead, it is no longer adhered to theanatomical site and permits easy removal.

In some embodiments, the bioadhesive is multifunctional and composed ofor contains radiopaque elements to allow for image-guided visualization,placement, and/or removal of it or the lead. Furthermore, the radiopaqueelements may be an additional safety feature, especially in the case oflong-term lead implantation, to monitor the location and position of thelead. In some arrangements, the bioadhesive may comprise entirely,partially, or a hybrid of radiopaque elements and/or imaging contrastagents. Such radiopaque elements may include, but are not limited to,radiopaque polymer agents, radiopaque agents (e.g., acrylic derivatives,inorganic salts, and high atomic number elements like bismuth, iodine,barium, etc.), contrast agent-eluting nano/microparticles, etc.

In some embodiments, the bioadhesive is electroconductive and/orpiezoelectric. In some aspects, the bioadhesive may compriseelectroconductive or piezoelectric materials (e.g., polypyrrole,polyaniline, polythiophene, etc.). In other aspects, the bioadhesive maybe a composite material containing electroconductive or piezoelectricelements, such as, but not limited to, carbon nanotubes, grapheneparticles, gold nanoparticles, silver nanoparticles, etc.Electroconductive or piezoelectric material properties can beadvantageous and otherwise beneficial. For example, to actsynergistically with electrical stimulation applied to a nerve forneuroregenerative and/or pain modulation therapy, but permitting morelocalized charge concentration to the anatomical region of interest.

In other embodiments, various therapeutic substances can be deliveredvia the electrode lead body to various locations along a trajectory nearor on the target injured nerve. Such substances can act synergisticallywith neuroregenerative therapy, acting by alternative mechanisms, and/orcan act to minimize pain, local inflammation, among others.

Kits

In some embodiments, a nerve treatment kit comprises two or more of thefollowing: a bioadhesive, an electrode lead having at least oneelectrode, a stimulation system, an insertion tool, and a user manual.In one arrangement, a kit may be deployed intraoperatively during orprior to the treatment of a nerve injury.

Although several embodiments and examples are disclosed herein, thepresent application extends beyond the specifically disclosedembodiments to other alternative embodiments and/or uses of the variousinventions and modifications, and/or equivalents thereof. It is alsocontemplated that various combinations or subcombinations of thespecific features and aspects of the embodiments may be made and stillfall within the scope of the inventions. Accordingly, various featuresand aspects of the disclosed embodiments can be combined with orsubstituted for one another in order to form varying modes of thedisclosed inventions. Thus, the scope of the various inventionsdisclosed herein should not be limited by any particular embodimentsdescribed above. While the embodiments disclosed herein are susceptibleto various modifications, and alternative forms, specific examplesthereof have been shown in the drawings and are described in detailherein. However, the inventions of the present application are notlimited to the particular forms or methods disclosed, but, to thecontrary, cover all modifications, equivalents, and alternatives fallingwithin the spirit and scope of the various embodiments described and theappended claims. Further, the disclosure herein of any particularfeature, aspect, method, property, characteristic, quality, attribute,element and/or the like in connection with an implementation orembodiment can be used in all other implementations or embodiments setforth herein.

In any methods disclosed herein, the acts or operations can be performedin any suitable sequence and are not necessarily limited to anyparticular disclosed sequence and not be performed in the order recited.Various operations can be described as multiple discrete operations inturn, in a manner that can be helpful in understanding certainembodiments; however, the order of description should not be construedto imply that these operations are order dependent. Additionally, anystructures described herein can be embodied as integrated components oras separate components. For purposes of comparing various embodiments,certain aspects and advantages of these embodiments are described. Notnecessarily all such aspects or advantages are achieved by anyparticular embodiment. Thus, for example, embodiments can be carried outin a manner that achieves or optimizes one advantage or group ofadvantages without necessarily achieving other advantages or groups ofadvantages.

The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “locating” a nerve, “coupling” an electrode to a nerve,“initiating” a stimulation procedure include “instructing locating,”“instructing coupling,” and “instructing initiating” etc., respectively.The ranges disclosed herein also encompass any and all overlap,sub-ranges, and combinations thereof. Language such as “up to,” “atleast,” “greater than,” “less than,” “between,” and the like includesthe number recited. Numbers preceded by a term such as “about” or“approximately” include the recited numbers and should be interpretedbased on the circumstances (e.g., as accurate as reasonably possibleunder the circumstances, for example ±5%, ±10%, ±15%, etc.). Forexample, “about 1 mm” includes “1 mm.” Phrases preceded by a term suchas “substantially” include the recited phrase and should be interpretedbased on the circumstances (e.g., as much as reasonably possible underthe circumstances). For example, “substantially rigid” includes “rigid,”and “substantially parallel” includes “parallel.”

The invention claimed is:
 1. An electrical lead assembly configured tobe inserted at least partially within an anatomy of a subject, theelectrical lead assembly comprising: at least one electrode configuredto be placed adjacent to targeted tissue of the subject to perform adesired procedure; a first insert located along a first portion of theelectrical lead assembly, wherein the first insert comprises plasticdeformation properties to (i) facilitate a shaping of the electricallead assembly along the first portion, and (ii) substantially maintain ashape following the shaping of the electrical lead assembly; wherein thefirst portion extends to a distal end of the electrical lead assembly;and wherein the first portion is configured to be shaped in order tomaintain a desired shape and position relative to the targeted tissue ofthe subject; a second insert located along a second portion of theelectrical lead assembly, wherein a rigidity of the second insert isgreater than a rigidity of the first insert, wherein the second portionextends to a proximal end of the electrical lead assembly; and at leastone outer covering configured to extend from the proximal end to thedistal end of the electrical lead assembly; wherein the at least oneelectrode is located along the first portion of the electrical leadassembly; wherein the proximal end is configured to be inserted into aport of an electrical stimulation device; wherein the first portion ofthe electrical lead assembly is configured to be shaped followingpercutaneous insertion into the anatomy of the subject by selectivelyexerting forces or moment along at least one portion of the firstportion; and wherein an elastic recoil force of the at least one outercovering is insufficient to overcome a plastic deformation of the firstinsert.
 2. The electrical lead assembly of claim 1, wherein an outerdiameter or other cross-sectional dimension of the electrical leadassembly is constant or substantially constant along a length of theelectrical lead assembly; and wherein the rigidity of the second insertis at least 100 times greater than the rigidity of the first insert. 3.The electrical lead assembly of claim 1, wherein an outer diameter orother cross-sectional dimension of the electrical lead assembly isconstant or substantially constant along a length of the electrical leadassembly.
 4. The electrical lead assembly of claim 3, wherein a maximumvariation in the outer diameter or other cross-sectional dimension is 5%along the length of the electrical lead assembly.
 5. The electrical leadassembly of claim 1, wherein the rigidity of the second insert is atleast 100 times greater than the rigidity of the first insert.
 6. Theelectrical lead assembly of claim 1, wherein the rigidity of the secondinsert is at least 2000 times greater than the rigidity of the firstinsert.
 7. The electrical lead assembly of claim 1, wherein the proximalend is configured to be inserted into a port of an electricalstimulation device without the need for an additional connector orcomponent.
 8. The electrical lead assembly of claim 1, wherein the atleast one electrode comprises a proximal electrode and a distalelectrode, wherein the proximal and distal electrodes are located alongthe first portion of the electrical lead assembly.
 9. The electricallead assembly of claim 1, wherein the at least one outer covering alongthe proximal end of the electrical lead assembly comprises a color thatis different than a distal portion of the at least one outer covering.10. The electrical lead assembly of claim 1, wherein the first portionof the electrical lead assembly is configured to be shaped usingforceps.
 11. The electrical lead assembly of claim 1, further comprisingthe electrical stimulation device.
 12. An electrical stimulation system,comprising: the electrical lead assembly of claim 1; and an electricalstimulation device; wherein the proximal end of the electrical leadassembly is configured to be inserted into a port of the electricalstimulation device without the need for an additional connector orcomponent.
 13. An electrical lead assembly configured to be inserted atleast partially within an anatomy of a subject, the electrical leadassembly comprising: at least one electrode; an insert located along adistal portion of the electrical lead assembly, wherein the insertcomprises plastic deformation properties to (i) facilitate a shaping ofthe electrical lead assembly along the distal portion, and (ii)substantially maintain a shape following the shaping of the electricallead assembly, wherein the distal portion extends to a distal end of theelectrical lead assembly; and at least one outer covering configured toextend from a proximal end to the distal end of the electrical leadassembly, wherein plastic deformation properties of the insert aregreater than elastic deformation properties of the at least onecovering; wherein the at least one electrode is located along the distalportion of the electrical lead assembly; wherein the distal portion ofthe electrical lead assembly is configured to be shaped followingpercutaneous insertion into the anatomy of the subject by selectivelyexerting forces or moment along at least one portion of the firstportion; wherein an outer diameter or other cross-sectional dimension ofthe electrical lead assembly is constant or substantially constant alonga length of the electrical lead assembly; and wherein an elastic recoilforce of the at least one outer covering is insufficient to overcome aplastic deformation of the insert.
 14. The electrical lead assembly ofclaim 13, wherein a maximum variation in the outer diameter or othercross-sectional dimension is 5% along the length of the electrical leadassembly.
 15. The electrical lead assembly of claim 13, wherein theproximal end of the electrical lead assembly comprises a proximalinsert, the proximal insert being more rigid than the insert.
 16. Theelectrical lead assembly of claim 15, wherein the rigidity of theproximal insert is at least 100 times greater than the rigidity of theinsert.
 17. The electrical lead assembly of claim 15, wherein therigidity of the proximal insert is at least 2000 times greater than therigidity of the insert.
 18. The electrical lead assembly of claim 13,wherein the proximal end is configured to be inserted into a port of anelectrical stimulation device.
 19. The electrical lead assembly of claim18, wherein the proximal end is configured to be inserted into a port ofan electrical stimulation device without the need for an additionalconnector or component.
 20. The electrical lead assembly of claim 13,wherein the at least one electrode comprises a proximal electrode and adistal electrode, wherein the proximal and distal electrodes are locatedalong a distal one-third of the electrical lead assembly.
 21. Theelectrical lead assembly of claim 13, wherein the at least one outercovering forms a substantially seamless surface along an exterior of theelectrical lead assembly.
 22. An electrical stimulation system,comprising: the electrical lead assembly of claim 13; and an electricalstimulation device; wherein the proximal end of the electrical leadassembly is configured to be inserted into a port of the electricalstimulation device without the need for an additional connector orcomponent.